Phenotypes associated with this allele

• Allele Symbol: Tg(tetO-cre)1Jaw
• Allele Name: transgene insertion 1, Jeffrey A Whitsett
• Allele ID: MGI:2679524
• Summary: 64 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
cn1	Trim71^tm1695Arte/Trim71^tm1695Arte Tg(tetO-cre)1Jaw/0 Gt(ROSA)26Sor^tm1(rtTA*M2)Jae/Gt(ROSA)26Sor^+	B6.Cg-Gt(ROSA)26Sor^tm1(rtTA*M2)Jae Trim71^tm1695Arte Tg(tetO-cre)1Jaw	MGI:7778319
cn2	Sox9^tm1Gsr/Sox9^tm1Gsr Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * 129P2/OlaHsd * C57BL/6	MGI:4888973
cn3	Foxa2^tm1Khk/Foxa2^tm1Khk Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * 129P2/OlaHsd * C57BL/6	MGI:3036449
cn4	Stat3^tm2Aki/Stat3^tm2Aki Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * 129P2/OlaHsd * C57BL/6	MGI:4888972
cn5	Met^tm1Sst/Met^tm1Sst Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * 129P2/OlaHsd * C57BL/6	MGI:4938180
cn6	Pten^tm2Mak/Pten^tm2Mak Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * 129P2/OlaHsd * C57BL/6 * C57BL/6J	MGI:4950587
cn7	Hif1a^tm3Rsjo/Hif1a^tm3Rsjo Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:4418552
cn8	Itga9^tm2Des/Itga9^tm2Des Tg(ACTA2-rtTA)#Des/0 Tg(tetO-cre)1Jaw/0	involves: 129 * 129S4/SvJae * C57BL/6	MGI:5448443
cn9	Acvr1^tm2.1Vlcg/Acvr1^+ Gt(ROSA)26Sor^tm1(rtTA*M2)Jae/Gt(ROSA)26Sor^+ Tg(tetO-cre)1Jaw/0	involves: 129 * 129S4/SvJae * C57BL/6 * C57BL/6NTac	MGI:5881968
cn10	Pten^tm1Hwu/Pten^tm1Hwu Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * 129S4/SvJae * C57BL/6 * FVB/N	MGI:4882116
cn11	Gt(ROSA)26Sor^tm1.1(rtTA2S*M2)Whsu/Gt(ROSA)26Sor^+ Ncstn^tm1.1Akli/Ncstn^tm1.1Akli Tg(tetO-cre)1Jaw/0	involves: 129 * 129S6/SvEvTac * C57BL/6	MGI:5779422
cn12	Cebpa^tm1Dgt/Cebpa^tm1Dgt Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * 129S6/SvEvTac * C57BL/6	MGI:4942158
cn13	Xbp1^tm2Glm/Xbp1^tm2Glm Tg(Adipoq-rtTA)2Zvw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * 129S6/SvEvTac * C57BL/6 * C57BL/6N	MGI:6376195
cn14	Foxm1^tm1Rhc/Foxm1^tm1Rhc Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * 129X1/SvJ * C57BL/6	MGI:4889055
cn15	Ctnnb1^tm1Mmt/Ctnnb1^+ Tg(Msx2-rtTA)885Lma/0 Tg(tetO-cre)1Jaw/0	involves: 129 * 129X1/SvJ * C57BL/6	MGI:5546509
cn16	Cebpa^tm1Gonz/Cebpa^tm1Gonz Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * 129X1/SvJ * C57BL/6 * FVB/N	MGI:3809493
cn17	Notch1^tm2Rko/Notch1^tm2Rko Tg(KRT14-rtTA)F42Efu/0 Tg(tetO-cre)1Jaw/0	involves: 129 * 129X1/SvJ * C57BL/6 * FVB/N	MGI:5512989
cn18	Klf5^tm1Jaw/Klf5^tm1Jaw Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * C57BL/6	MGI:3806650
cn19	Itga3^tm1Hap/Itga3^tm1Hap Tg(SFTPC-rtTA)5Jaw/? Tg(tetO-cre)1Jaw/?	involves: 129 * C57BL/6	MGI:3833133
cn20	Itga3^tm1Hap/Itga3^tm1Hap Tg(CAG-Bgeo/GFP)21Lbe/? Tg(SFTPC-rtTA)5Jaw/? Tg(tetO-cre)1Jaw/?	involves: 129 * C57BL/6	MGI:3833134
cn21	Tg(CAG-cat,-Il18)#Thos/0 Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * C57BL/6	MGI:5688535
cn22	Gt(ROSA)26Sor^tm1(rtTA,EGFP)Nagy/Gt(ROSA)26Sor^+ Rbpj^tm1Hon/Rbpj^tm1Hon Tg(tetO-cre)1Jaw/0	involves: 129 * C57BL/6	MGI:4418250
cn23	Vegfa^tm2Gne/Vegfa^tm2Gne Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * C57BL/6	MGI:4938179
cn24	Vegfa^tm2Gne/Vegfa^+ Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * C57BL/6	MGI:4938194
cn25	Gt(ROSA)26Sor^tm4(Wnt7b)Flng/Gt(ROSA)26Sor^+ Tg(Runx2-rtTA*M2)#Flng/0 Tg(tetO-cre)1Jaw/0	involves: 129 * C57BL/6	MGI:5613585
cn26	Eif4b^tm1.1Smoc/Eif4b^tm1.1Smoc Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * C57BL/6	MGI:6790452
cn27	Elavl1^tm1Lix/Elavl1^tm1Lix Tg(Scgb1a1-rtTA)2Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * C57BL/6	MGI:5543893
cn28	Eif4b^tm1.1Smoc/Eif4b^+ Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * C57BL/6	MGI:6790454
cn29	Cad^tm1c(KOMP)Wtsi/Cad^tm1c(KOMP)Wtsi Tg(Adipoq-rtTA)2Zvw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * C57BL/6 * C57BL/6N	MGI:6376235
cn30	Tulp3^tm1c(EUCOMM)Hmgu/Tulp3^tm1c(EUCOMM)Hmgu Tg(Pax8-rtTA2S*M2)1Koes/0 Tg(tetO-cre)1Jaw/0	involves: 129 * C57BL/6 * C57BL/6N * DBA * SJL	MGI:6392317
cn31	Cad^tm1c(KOMP)Wtsi/Cad^tm1c(KOMP)Wtsi Tg(Adipoq-rtTA)2Zvw/0 Tg(tetO-cre)1Jaw/0 Tg(tetO-Xbp1_is)#Pesch/0	involves: 129 * C57BL/6 * C57BL/6N * FVB/N	MGI:6376231
cn32	Gt(ROSA)26Sor^tm1(MAML1)Wsp/Gt(ROSA)26Sor^+ Tg(KRT14-rtTA)F42Efu/0 Tg(tetO-cre)1Jaw/0	involves: 129 * C57BL/6 * FVB	MGI:5512988
cn33	Adam17^tm1.1Wesh/Adam17^tm1.1Wesh Tg(Scgb1a1-rtTA)2Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * C57BL/6 * FVB/N	MGI:5571468
cn34	Tg(Scgb1a1-rtTA)2Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * C57BL/6 * FVB/N	MGI:5301912
cn35	Drosha^tm1Ghan/Drosha^tm1Ghan Tg(KRT5-rtTA)1Glk/0 Tg(tetO-cre)1Jaw/0	involves: 129 * C57BL/6 * FVB/N	MGI:5431582
cn36	Angpt1^tm1.1Seq/Angpt1^tm1.1Seq Angpt2^tm1c(KOMP)Seq/Angpt2^tm1c(KOMP)Seq Gt(ROSA)26Sor^tm1(rtTA,EGFP)Nagy/? Tg(tetO-cre)1Jaw/0	involves: 129 * C57BL/6NCr	MGI:5613965
cn37	Tek^tm1.1Vlcg/Tek^tm1.1Vlcg Gt(ROSA)26Sor^tm1(rtTA,EGFP)Nagy/? Tg(tetO-cre)1Jaw/0	involves: 129 * C57BL/6NCr	MGI:5613966
cn38	Ctnnb1^tm2Kem/Ctnnb1^tm2Kem Pparg^tm1.1(tTA)Jmgr/Pparg^+ Tg(tetO-cre)1Jaw/0	involves: 129P2/OlaHsd * 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:5581951
cn39	Ctnnb1^tm2Kem/Ctnnb1^+ Pparg^tm1.1(tTA)Jmgr/Pparg^+ Tg(tetO-cre)1Jaw/0	involves: 129P2/OlaHsd * 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:5581952
cn40	Ctnnb1^tm2Kem/Ctnnb1^tm2Kem Pparg^tm1.1(tTA)Jmgr/Pparg^+ Tg(tetO-cre)1Jaw/0 Tg(tetO-HIST1H2BJ/GFP)47Efu/0	involves: 129P2/OlaHsd * 129S1/Sv * 129X1/SvJ * C57BL/6 * CD-1	MGI:5581950
cn41	Ctnnb1^tm1Mmt/Ctnnb1^+ Pparg^tm1.1(tTA)Jmgr/Pparg^+ Tg(tetO-cre)1Jaw/0	involves: 129P2/OlaHsd * 129X1/SvJ * C57BL/6	MGI:5581956
cn42	Drosha^tm1Litt/Drosha^tm1Litt Tg(KRT5-rtTA)1Glk/0 Tg(tetO-cre)1Jaw/0	involves: 129P2/OlaHsd * C57BL/6 * FVB/N	MGI:5431584
cn43	Nedd4l^tm1.1Hkb/Nedd4l^tm1.1Hkb Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129P2/OlaHsd * C57BL/6 * FVB/N * SJL	MGI:4941006
cn44	Lama5^tm1Jhm/Lama5^tm2Jhm Tg(SFTPC-rtTA)5Jaw/? Tg(tetO-cre)1Jaw/?	involves: 129S1/Sv * 129X1/SvJ	MGI:3613082
cn45	Fgfr1^tm1Jpa/Fgfr1^tm1Jpa Fgfr2^tm1Dor/Fgfr2^tm1Dor Tg(Msx2-rtTA)888Lma/0 Tg(tetO-cre)1Jaw/0	involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:5694225
cn46	Ctnnb1^tm2Kem/Ctnnb1^tm2Kem Tg(KRT5-rtTA)#Glk/0 Tg(tetO-cre)1Jaw/0	involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * FVB/N	MGI:5538307
cn47	Adgrf5^tm1.1Bstc/Adgrf5^tm1.2Bstc Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129S4/SvJae * C57BL/6 * C57BL/6J	MGI:5490536
cn48	Tulp3^tm1c(EUCOMM)Hmgu/Tulp3^tm1c(EUCOMM)Hmgu Pkd1^tm2Ggg/Pkd1^+ Tg(Pax8-rtTA2S*M2)1Koes/0 Tg(tetO-cre)1Jaw/0	involves: 129S4/SvJae * C57BL/6 * C57BL/6N * DBA * SJL	MGI:6392322
cn49	Tulp3^tm1c(EUCOMM)Hmgu/Tulp3^tm1c(EUCOMM)Hmgu Pkd1^tm2Ggg/Pkd1^tm2Ggg Tg(Pax8-rtTA2S*M2)1Koes/0 Tg(tetO-cre)1Jaw/0	involves: 129S4/SvJae * C57BL/6 * C57BL/6N * DBA * SJL	MGI:6392333
cn50	Tulp3^tm1c(EUCOMM)Hmgu/Tulp3^+ Pkd1^tm2Ggg/Pkd1^tm2Ggg Tg(Pax8-rtTA2S*M2)1Koes/0 Tg(tetO-cre)1Jaw/0	involves: 129S4/SvJae * C57BL/6 * C57BL/6N * DBA * SJL	MGI:6392330
cn51	Pkd1^tm2Ggg/Pkd1^tm2Ggg Tg(Pax8-rtTA2S*M2)1Koes/0 Tg(tetO-cre)1Jaw/0	involves: 129S4/SvJae * C57BL/6 * C57BL/6N * DBA * SJL	MGI:6392328
cn52	Pkd1^tm2Ggg/Pkd1^+ Tg(Pax8-rtTA2S*M2)1Koes/0 Tg(tetO-cre)1Jaw/0	involves: 129S4/SvJae * C57BL/6 * C57BL/6N * DBA * SJL	MGI:6392326
cn53	Tg(KRT5-rtTA)#Glk/0 Tg(tetO-cre)1Jaw/0 Wls^tm1.1Lan/Wls^tm1.1Lan	involves: 129S6/SvEvTac * C57BL/6 * FVB/N	MGI:5538309
cn54	Dicer1^tm1Smr/Dicer1^tm1Smr Tg(KRT5-rtTA)1Glk/0 Tg(tetO-cre)1Jaw/0	involves: 129S7/SvEvBrd * C57BL/6 * FVB/N	MGI:5431583
cn55	Kras^tm4Tyj/Kras^+ Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129/Sv * C57BL/6	MGI:3716394
cn56	Bdnf^tm3Jae/Bdnf^tm3Jae Tg(Eno2tTA)5030Nes/0 Tg(tetO-cre)1Jaw/0	involves: 129/Sv * C57BL/6 * ICR * SJL	MGI:3051987
cn57	Gt(ROSA)26Sor^tm1(EYFP)Cos/Gt(ROSA)26Sor^+ Hprt1^tm1(Ins2-HBEGF)Herr/Y Tg(Gcg-rtTA)#Herr/0 Tg(tetO-cre)1Jaw/0	involves: 129X1/SvJ * C57BL/6	MGI:5567830
cn58	Adam17^tm1.1Wesh/Adam17^tm1.1Wesh Tg(Scgb1a1-rtTA)2Jaw/0 Tg(tetO-cre)1Jaw/0 Twist2^tm1.1(cre)Dor/Twist2^+	involves: 129X1/SvJ * C57BL/6 * FVB/N	MGI:5571470
cn59	Tg(KRT5-rtTA)#Glk/0 Tg(tetO-cre)1Jaw/0 Wnt10a^tm1Smr/Wnt10a^tm1Smr	involves: 129X1/SvJ * C57BL/6 * FVB/N	MGI:5905988
cn60	Pcyt1a^tm1Irt/Pcyt1a^tm1Irt Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/Tg(tetO-cre)1Jaw	involves: C57BL/6J * FVB/N	MGI:4940890
cn61	Foxa2^tm1.1(rtTa)Moon/Foxa2^tm1.1(rtTa)Moon Gt(ROSA)26Sor^tm1Sor/? Tg(tetO-cre)1Jaw/?	involves: C57BL/6 * SJL	MGI:3713390
cn62	Shh^tm1Amc/Shh^tm2Amc Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: FVB/N	MGI:3051584
cn63	Shh^tm2Amc/Shh^tm2Amc Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: FVB/N	MGI:3051583
cn64	Foxa2^tm1Khk/Foxa2^tm1Khk Tg(Scgb1a1-rtTA)1Jaw/0 Tg(tetO-cre)1Jaw/0	Not Specified	MGI:3036450

Genotype
MGI:7778319

cn1

• Allelic Composition: Trim71^tm1695Arte/Trim71^tm1695Arte; Tg(tetO-cre)1Jaw/0; Gt(ROSA)26Sor^{tm1(rtTA*M2)Jae}/Gt(ROSA)26Sor⁺
• Genetic Background: B6.Cg-Gt(ROSA)26Sor^{tm1(rtTA*M2)Jae} Trim71^tm1695Arte Tg(tetO-cre)1Jaw

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

embryo

abnormal neural tube morphology ( J:335575 )

• doxycycline treatment at E5.5 results in completely penetrant neural tube defects at E12.5

• however, doxycycline treatment at P0.5 results in normal brain development

nervous system

abnormal neural tube morphology ( J:335575 )

• doxycycline treatment at E5.5 results in completely penetrant neural tube defects at E12.5

• however, doxycycline treatment at P0.5 results in normal brain development

Genotype
MGI:4888973

cn2

• Allelic Composition: Sox9^tm1Gsr/Sox9^tm1Gsr; Tg(SFTPC-rtTA)5Jaw/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129 * 129P2/OlaHsd * C57BL/6

respiratory system

respiratory system phenotype ( J:95910 )

N • mice treated with doxycycline from E0.5 display normal postnatal survival and normal lung morphology with no detectable changes in the cellular differentiation or development of peripheral lung epithelium at all stages analyzed (E12.5 to adulthood)

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:95910 )

N • mice treated with doxycycline from E0.5 display normal survival and repair after hyperoxia-induced lung injury (95% oxygen for 3 days) relative to control littermates

Genotype
MGI:3036449

cn3

• Allelic Composition: Foxa2^tm1Khk/Foxa2^tm1Khk; Tg(SFTPC-rtTA)5Jaw/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129 * 129P2/OlaHsd * C57BL/6

mortality/aging

neonatal lethality, incomplete penetrance ( J:93473 )

• most mice treated with doxycycline from E0 die on P1

postnatal lethality, incomplete penetrance ( J:88601 , J:93473 )

• 50% of mice treated with doxycycline from E0 through P16 died within 30 days of birth (J:88601)

• only 46% of mice treated with doxycycline from E0 survive to P5 (J:93473)

hematopoietic system

increased neutrophil cell number ( J:88601 )

• observed in bronchoalveolar lavage from mice treated with doxycycline from E0 through P16

increased macrophage cell number ( J:88601 )

• observed in bronchoalveolar lavage from mice treated with doxycycline from E0 through P16

immune system

increased neutrophil cell number ( J:88601 )

• observed in bronchoalveolar lavage from mice treated with doxycycline from E0 through P16

increased macrophage cell number ( J:88601 )

• observed in bronchoalveolar lavage from mice treated with doxycycline from E0 through P16

respiratory system

pulmonary vascular congestion ( J:93473 )

• mice treated with doxycycline from E0 and found to be in distress or moribund on P1 display pulmonary congestion

impaired lung alveolus development ( J:88601 , J:93473 )

• impaired alveogenesis marked by fewer peripheral lung saccules and decreased alveolar septation; apparent at 3 days of age in mice treated with doxycycline from E0 through P16 (J:88601)

abnormal lung saccule morphology ( J:93473 )

• at E18.5, mice treated with doxycycline from E0 display immature peripheral lung saccules, resembling those normally seen at E16-E17

abnormal pulmonary alveolus epithelial cell morphology ( J:93473 )

• at E18.5, squamous type I cells are missing, alveolar walls are thickened and lined by immature cuboidal type II cells, cytoplasmic glycogen is dispersed, and apical microvilli are absent

• however, no evidence of capillary leakage or endothelial cell abnormalities are observed

absent type I pneumocytes ( J:93473 )

• at E18.5, no squamous type I cells are observed in mice treated with doxycycline from E0

abnormal type II pneumocyte morphology ( J:93473 )

• at E18.5, mice treated with doxycycline from E0 show absence of lamellar bodies in alveolar type II cells

absent alveolar lamellar bodies ( J:93473 )

increased pulmonary alveolus wall thickness ( J:93473 )

• at E18.5, mice treated with doxycycline from E0 show thickened alveolar walls lined by immature cuboidal type II cells

atelectasis ( J:93473 )

• mice treated with doxycycline from E0 and found to be in distress or moribund on P1 display focal or extensive atelectasis

dilated respiratory conducting tube ( J:88601 )

• increased airspace in mice prenatally treated with doxycycline

• postnatal treatment with doxycycline also resulted in increased airspace but to a lesser extent

• normal prenatal lung morphogenesis

pulmonary hyaline membrane formation ( J:93473 )

• mice treated with doxycycline from E0 and found to be in distress or moribund on P1 display hyaline membrane formation

increased respiratory mucosa goblet cell number ( J:88601 )

• goblet cell hyperplasia, associated with the accumulation of both neutral and acidic mucins, observed in mice treated with doxycycline from E0 through P16

respiratory distress ( J:93473 )

• ~50% of mice treated with doxycycline from E0 develop severe respiratory distress within 2-3 hrs of birth

abnormal surfactant composition ( J:93473 )

• at E18.5, the fractional content of phosphatidylcholine (PC) and saturated PC are markdely reduced, whereas that of phosphatidylethanolamine, sphingomyelin, and phosphatidylserine is increased in the lungs of mice treated with doxycycline from E0

abnormal surfactant secretion ( J:93473 )

• SP-A, SP-B, and SP-C mRNAs are significantly decreased at E18.5

• the active SP-B peptide is markedly decreased in lung homogenates prior to birth

• SP-D mRNAs are significantly increased at E18.5

decreased surfactant secretion ( J:93473 )

• at E18.5, no secreted surfactant is detected in the air spaces of mice treated with doxycycline from E0

homeostasis/metabolism

cyanosis ( J:93473 )

• ~50% of mice treated with doxycycline from E0 display cyanosis

behavior/neurological

pup cannibalization ( J:93473 )

♀ • newborn mice are frequently cannibalized by the mother

cardiovascular system

pulmonary vascular congestion ( J:93473 )

• mice treated with doxycycline from E0 and found to be in distress or moribund on P1 display pulmonary congestion

Genotype
MGI:4888972

cn4

• Allelic Composition: Stat3^tm2Aki/Stat3^tm2Aki; Tg(SFTPC-rtTA)5Jaw/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129 * 129P2/OlaHsd * C57BL/6

mortality/aging

mortality/aging ( J:87622 )

N • under normoxic conditions, mice treated with doxycycline from E0 to P25 exhibit no differences in survival at E18.5 or after birth relative to control littermates

homeostasis/metabolism

abnormal cytokine level ( J:87622 )

• after exposure to hyperoxia, doxycycline-treated mice display increased IL-1beta, IL-6, and MIP-2 levels in lung tissue relative to control littermates

increased susceptibility to injury ( J:87622 )

• when doxycycline is administered from E0 to P25, adult mice are more susceptible to hyperoxia-induced (95% O2 for 65 hrs) lung injury than oxygen-exposed control littermates, displaying an earlier onset of respiratory symptoms, significantly reduced survival, and severe lung injury as shown by hemorrhage, perivascular and lymphatic edema, loss of bronchiolar and alveolar epithelia, severe epithelial cell necrosis, thickened alveoli, extensive inflammation and frequent airspace enlargement

• intratracheal treatment with exogenous surfactant protein B improves survival and lung histology in doxycycline-treated mice 4 days after hyperoxia exposure

respiratory system

respiratory system phenotype ( J:87622 )

N • under normoxic conditions, mice treated with doxycycline from E0 to P25 exhibit normal lung size and morphology and normal pulmonary mechanics relative to control littermates

abnormal lung vasculature morphology ( J:87622 )

• after exposure to hyperoxia, doxycycline-treated mice display loss of alveolar capillary membrane integrity, perivascular edema, and severe vascular cell necrosis relative to control littermates

lung inflammation ( J:87622 )

• after exposure to hyperoxia, doxycycline-treated mice display increased infiltration by polymorphonuclear cells and alveolar macrophages along with an increased production of IL-1beta, IL-6, and MIP-2 relative to control littermates

abnormal pulmonary alveolus epithelial cell morphology ( J:87622 )

• after exposure to hyperoxia, doxycycline-treated mice display widespread alveolar epithelial cell necrosis without apoptosis, hyaline membrane formation, loss of alveolar capillary membrane integrity, and increased inflammation consistent with severe epithelial cell injury

decreased type II pneumocyte number ( J:87622 )

• after exposure to hyperoxia, staining for proSP-C, a selective marker for type II cells, is decreased in doxycycline-treated mice

pulmonary epithelial necrosis ( J:87622 )

• after exposure to hyperoxia, doxycycline-treated mice display widespread alveolar epithelial cell necrosis without apoptosis

• after exposure to hyperoxia, doxycycline-treated mice display extensive epithelial cell necrosis in the bronchiolar epithelium

pulmonary hyaline membrane formation ( J:87622 )

• after exposure to hyperoxia, doxycycline-treated mice display hyaline membrane formation

increased lung elastance ( J:87622 )

• after exposure to hyperoxia, doxycycline-treated mice display significantly increased lung elastance

increased lung tissue damping ( J:87622 )

• after exposure to hyperoxia, doxycycline-treated mice display significantly increased tissue damping

respiratory distress ( J:87622 )

• doxycycline-treated mice develop acute respiratory distress within 72 hrs of hyperoxia, unlike control littermates which develop severe respiratory symptoms after 5 or more days of continued exposure

abnormal respiratory mechanics ( J:87622 )

• after exposure to hyperoxia, doxycycline-treated mice display altered pulmonary mechanics, indicating a decline in pulmonary function

• however, hysteresivity and newtonian resistance remain unaffected

increased airway resistance ( J:87622 )

• after exposure to hyperoxia, doxycycline-treated mice display a significant increase in airway resistance relative to control littermates

decreased lung compliance ( J:87622 )

• after exposure to hyperoxia, doxycycline-treated mice display reduced lung compliance relative to control littermates

respiratory failure ( J:87622 )

• doxycycline-treated mice exhibit respiratory failure after relatively short periods of hyperoxia

abnormal surfactant secretion ( J:87622 )

• after exposure to hyperoxia, doxycycline-treated mice show significantly increased BALF protein content and reduced alveolar surfactant phospholipid (saturated phosphatidylcholine) pool sizes relative to control littermates

• after exposure to hyperoxia, SP-B is undetectable while SP-A is significantly decreased in alveolar lavage of doxycycline-treated mice

immune system

abnormal cytokine level ( J:87622 )

• after exposure to hyperoxia, doxycycline-treated mice display increased IL-1beta, IL-6, and MIP-2 levels in lung tissue relative to control littermates

lung inflammation ( J:87622 )

• after exposure to hyperoxia, doxycycline-treated mice display increased infiltration by polymorphonuclear cells and alveolar macrophages along with an increased production of IL-1beta, IL-6, and MIP-2 relative to control littermates

cardiovascular system

abnormal lung vasculature morphology ( J:87622 )

• after exposure to hyperoxia, doxycycline-treated mice display loss of alveolar capillary membrane integrity, perivascular edema, and severe vascular cell necrosis relative to control littermates

Genotype
MGI:4938180

cn5

• Allelic Composition: Met^tm1Sst/Met^tm1Sst; Tg(SFTPC-rtTA)5Jaw/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129 * 129P2/OlaHsd * C57BL/6

respiratory system

abnormal lung development ( J:124125 )

• newborn mice exposed to doxycycline from E14.5 to birth display defective distal lung saccular development due to reduced primary septation

abnormal lung saccule morphology ( J:124125 )

• newborn mice exposed to doxycycline from E14.5 to birth display dilated distal airspaces with only few primary septae, unlike wild-type controls where extensive numbers of saccules are observed

Genotype
MGI:4950587

cn6

• Allelic Composition: Pten^tm2Mak/Pten^tm2Mak; Tg(SFTPC-rtTA)5Jaw/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129 * 129P2/OlaHsd * C57BL/6 * C57BL/6J

mortality/aging

decreased survivor rate ( J:127405 )

• ~10% of mice treated with doxycycline in utero (E10-E16) survive to adulthood but develop spontaneous lung tumors, not observed in wild-type controls during a 90-wk observation period

• the cancer-free survival rates for prenatally doxycycline-treated mice are significantly lower than for controls

neonatal lethality, incomplete penetrance ( J:127405 )

• ~90% of mice treated with doxycycline in utero (E10-E16) die within 2 hrs of birth due to respiratory failure

• in contrast, mice treated with doxycycline postnatally (P21-P27 or P84-P90) do not show any neonatal lethality

homeostasis/metabolism

cyanosis ( J:127405 )

• neonates treated with doxycycline in utero (E10-E16) display a cyanotic skin color

hypoxia ( J:127405 )

• neonates treated with doxycycline in utero (E10-E16) display significant hypoxia

respiratory acidosis ( J:127405 )

• neonates treated with doxycycline in utero (E10-E16) display respiratory acidosis

increased incidence of tumors by chemical induction ( J:127405 )

• following urethane treatment, 94% (17 of 18) of mice treated with doxycycline in utero (E10-E16) developed lung tumors (one lung adenocarcinoma, the rest being lung adenomas) relative to only 42% (11 of 26) of wild-type controls (all lung adenomas); also seen in mice treated with doxycycline postnatally (P21-P27)

• both prenatal and postnatal doxycycline treatment resulted in significantly increased numbers and sizes of urethane-induced lung tumors relative to those seen in wild-type controls

respiratory system

pulmonary hyperplasia ( J:127405 )

• at birth, mice treated with doxycycline in utero (E10-E16) show a 1.5-fold increase in total lung cell numbers relative to controls

• at E19.5, the numbers of both alveolar epithelial cells and mesenchymal cells are significantly increased due to enhanced cell proliferation rather than reduced apoptosis

respiratory acidosis ( J:127405 )

• neonates treated with doxycycline in utero (E10-E16) display respiratory acidosis

increased lung adenocarcinoma incidence ( J:127405 )

• 13 of 14 mice treated with doxycycline in utero (E10-E16) developed lung adenocarcinomas, not observed in any wild-type controls during a 90-wk observation period

• 13 of 15 (87%) of mice treated with doxycycline postnatally (P21-P27) developed spontaneous lung adenocarcinomas, not observed in any wild-type controls during the 40- to 70-wk observation period

• notably, Kras was mutated in 33% of spontaneous lung adenocarcinomas observed in P21-P27 doxycycline treated mice

increased lung squamous cell carcinoma incidence ( J:127405 )

• 1 of 14 mice treated with doxycycline in utero (E10-E16) developed a lung squamous cell carcinoma

abnormal lung development ( J:127405 )

• mice treated with doxycycline in utero (E10-E16) display delayed lung development at the terminal sac stage (E17.5 to P0) relative to control mice

increased mesenchymal cell proliferation involved in lung development ( J:127405 )

• at E19.5, mice treated with doxycycline in utero (E10-E16) show an expanded mesenchymal cell population, due to increased numbers of myofibroblast precursors in the septa

• mesenchymal cell numbers are significantly increased due to enhanced cell proliferation rather than reduced apoptosis

abnormal lung saccule morphology ( J:127405 )

• at the terminal sac stage (E17.5 to P0), mice treated with doxycycline in utero (E10-E16) display fewer saccular structures with a significant delay in the dilatation of the distal tubules relative to control mice

• at birth, mice treated with doxycycline in utero (E10-E16) display septal hyperplasia with increased mesenchymal cells and reduced airspaces relative to controls

small lung saccule ( J:127405 )

• at birth, mice treated with doxycycline in utero (E10-E16) display reduced airspaces relative to controls

increased bronchioalveolar stem cell number ( J:127405 )

• at 8 weeks of age, mice treated with doxycycline postnatally (P21-P27) show a 5.2-fold increase in BASCs and a 4.0-fold increase in side population cells relative to wild-type controls; similar increases are observed in E10-E16 doxycycline treated mice

bronchiolar epithelial hyperplasia ( J:127405 )

• neonates treated with doxycycline in utero (E10-E16) display significant bronchiolar epithelial hyperplasia relative to controls

• mice treated with doxycycline postnatally (P21-P27 or P84-P90) display mild bronchiolar epithelial hyperplasia relative to controls; however no significant differences in bronchiolar epithelial differentiation are observed

abnormal pulmonary alveolus epithelial cell morphology ( J:127405 )

• at E19.5, mice treated with doxycycline in utero (E10-E16) display increased numbers of undifferentiated cuboidal alveolar epithelial cells of enlarged size relative to controls

• mice treated with doxycycline postnatally (P21-P27 or P84-P90) display mild alveolar epithelial hyperplasia and increased cell size of alveolar epithelial cells relative to controls; however, no significant differences in alveolar epithelial differentiation are observed

abnormal type I pneumocyte morphology ( J:127405 )

• at E19.5, mice treated with doxycycline in utero (E10-E16) display impaired type I cell differentiation, as shown by severely reduced aquaporin-5 (AQP5) immunostaining relative to controls

abnormal type II pneumocyte morphology ( J:127405 )

• at E19.5, mice treated with doxycycline in utero (E10-E16) display immature rounded to cuboidal cells with poorly differentiated cytoplasm, rare apical microvilli, few lamellar bodies, and severely reduced SP-C immunostaining relative to control mice

• at P0, mice treated with doxycycline in utero (E10-E16) also display PAS positivity unlike wild-type control mice

decreased alveolar lamellar body number ( J:127405 )

• at E19.5, mice treated with doxycycline in utero (E10-E16) display fewer lamellar bodies than control mice

abnormal alveolocapillary membrane morphology ( J:127405 )

• at E19.5, mice treated with doxycycline in utero (E10-E16) display a much thicker blood-air barrier than control mice

respiratory distress ( J:127405 )

• neonates treated with doxycycline in utero (E10-E16) display irregular breathing and gasping

respiratory failure ( J:127405 )

• ~90% of mice treated with doxycycline in utero (E10-E16) die of respiratory failure

decreased surfactant secretion ( J:127405 )

• at E19.5, mice treated with doxycycline in utero (E10-E16) display a significant reduction in the expression levels of surfactant proteins A (SP-A), SP-B, SP-C and SP-D relative to control mice

neoplasm

increased incidence of tumors by chemical induction ( J:127405 )

• following urethane treatment, 94% (17 of 18) of mice treated with doxycycline in utero (E10-E16) developed lung tumors (one lung adenocarcinoma, the rest being lung adenomas) relative to only 42% (11 of 26) of wild-type controls (all lung adenomas); also seen in mice treated with doxycycline postnatally (P21-P27)

• both prenatal and postnatal doxycycline treatment resulted in significantly increased numbers and sizes of urethane-induced lung tumors relative to those seen in wild-type controls

increased lung adenocarcinoma incidence ( J:127405 )

• 13 of 14 mice treated with doxycycline in utero (E10-E16) developed lung adenocarcinomas, not observed in any wild-type controls during a 90-wk observation period

• 13 of 15 (87%) of mice treated with doxycycline postnatally (P21-P27) developed spontaneous lung adenocarcinomas, not observed in any wild-type controls during the 40- to 70-wk observation period

• notably, Kras was mutated in 33% of spontaneous lung adenocarcinomas observed in P21-P27 doxycycline treated mice

increased lung squamous cell carcinoma incidence ( J:127405 )

• 1 of 14 mice treated with doxycycline in utero (E10-E16) developed a lung squamous cell carcinoma

cellular

increased mesenchymal cell proliferation involved in lung development ( J:127405 )

• at E19.5, mice treated with doxycycline in utero (E10-E16) show an expanded mesenchymal cell population, due to increased numbers of myofibroblast precursors in the septa

• mesenchymal cell numbers are significantly increased due to enhanced cell proliferation rather than reduced apoptosis

growth/size/body

pulmonary hyperplasia ( J:127405 )

• at birth, mice treated with doxycycline in utero (E10-E16) show a 1.5-fold increase in total lung cell numbers relative to controls

• at E19.5, the numbers of both alveolar epithelial cells and mesenchymal cells are significantly increased due to enhanced cell proliferation rather than reduced apoptosis

Genotype
MGI:4418552

cn7

• Allelic Composition: Hif1a^tm3Rsjo/Hif1a^tm3Rsjo; Tg(SFTPC-rtTA)5Jaw/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129 * 129S1/Sv * 129X1/SvJ * C57BL/6

mortality/aging

neonatal lethality, incomplete penetrance ( J:143384 )

• all mice die within an hour of birth when exposed to doxycycline 8 days prior to parturition

• 85% of mice die within an hour of birth when exposed to doxycycline 4 of 6 days prior to parturition

respiratory system

increased lung weight ( J:143384 )

• at birth when mice are exposed to doxycycline prior to parturition

abnormal pulmonary alveolus morphology ( J:143384 )

• when mice are exposed to doxycycline prior to parturition, mice exhibit reduced alveolar airspaces unlike wild-type mice

abnormal pulmonary alveolus epithelial cell morphology ( J:143384 )

• when mice are exposed to doxycycline prior to parturition, the alveolar surface is lined with immature pneumocytes unlike in wild-type mice

abnormal type II pneumocyte morphology ( J:143384 )

• when mice are exposed to doxycycline prior to parturition, the alveolar septa has only a few scattered type II cells unlike in wild-type mice

atelectasis ( J:143384 )

• at birth when mice are exposed to doxycycline prior to parturition

thick pulmonary interalveolar septum ( J:143384 )

• at birth when mice are exposed to doxycycline prior to parturition

respiratory distress ( J:143384 )

• at birth when mice are exposed to doxycycline prior to parturition

abnormal surfactant secretion ( J:143384 )

• when mice are exposed to doxycycline prior to parturition

homeostasis/metabolism

cyanosis ( J:143384 )

• at birth when mice are exposed to doxycycline prior to parturition

growth/size/body

increased lung weight ( J:143384 )

• at birth when mice are exposed to doxycycline prior to parturition

Genotype
MGI:5448443

cn8

• Allelic Composition: Itga9^tm2Des/Itga9^tm2Des; Tg(ACTA2-rtTA)#Des/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129 * 129S4/SvJae * C57BL/6

respiratory system

respiratory system phenotype ( J:190074 )

N • mice exhibit normal airway epithelium morphology and no evidence of inflammation

abnormal respiratory system morphology ( J:190074 )

• methacholine-treated mice exhibit increased narrowing in airways compared with control mice

• lung slices treated with methacholine in vitro exhibit increased narrowing compared with control slices

• spermine has no increase in contraction unlike in control samples

• however, putrescine has no effect on airway contraction

abnormal respiratory system physiology ( J:190074 )

• excised tracheal rings (with or without epithelium) treated with methacholine exhibit increased in vitro force generation compared with control rings

• lung slices and tracheal rings exhibit increased contractile response to 5-HT compared with control samples

increased airway responsiveness ( J:190074 )

• in response to acetylcholine

Genotype
MGI:5881968

cn9

• Allelic Composition: Acvr1^tm2.1Vlcg/Acvr1⁺; Gt(ROSA)26Sor^{tm1(rtTA*M2)Jae}/Gt(ROSA)26Sor⁺; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129 * 129S4/SvJae * C57BL/6 * C57BL/6NTac

skeleton

increased bone ossification ( J:239136 )

• mice treated with doxycycline at 1 month of age for 3 days then injected with cardiotoxin into the quadriceps muscle to induce inflammation and muscle damage develop large heterotopic ossification tissue masses

• treatment of cardiotoxin-induced muscle injury with palovarotene diminishes heterotopic ossification formation by more than 80%

behavior/neurological

abnormal motor capabilities/coordination/movement ( J:239136 )

• about 14 days after heterotopic ossification induction by injury in doxycycline treated mice, movement of affected legs is impaired

• treatment with palovarotene of mice with cardiotoxin-induced muscle injury rescues the impaired movement

Genotype
MGI:4882116

cn10

• Allelic Composition: Pten^tm1Hwu/Pten^tm1Hwu; Tg(SFTPC-rtTA)5Jaw/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129 * 129S4/SvJae * C57BL/6 * FVB/N

respiratory system

abnormal respiratory epithelium morphology ( J:146355 )

• doxycyline treated mice exhibit an increase in proliferation of epithelial cells lining conducting airways

abnormal lung epithelium morphology ( J:146355 )

• papillary epithelial hyperplasia is seen as early as 4-6 weeks of age in mice treated with doxycycline

• papillary epithelial hyperplasia is characterized by a hypercellular epithelium lining papillae with fibrovascular cores that protrude into the airway lumens

increased club cell number ( J:146355 )

• doxycyline treated mice exhibit an increase in proliferation of nonciliated bronchial and bronchiolar Clara cells

bronchiolar epithelial hyperplasia ( J:146355 )

• mice treated with doxycycline exhibit bronchiolar epithelial hyperplasia, producing papillae composed of fibrovascular cores lined by a hypercellular epithelium protruding into the airway lumens consisting of enlarged cells

bronchial epithelial hyperplasia ( J:146355 )

• mice treated with doxycycline exhibit bronchial epithelial hyperplasia, producing papillae composed of fibrovascular cores lined by a hypercellular epithelium protruding into the airway lumens consisting of enlarged cells

endocrine/exocrine glands

increased solitary pulmonary neuroendocrine cell number ( J:146355 )

• pulmonary neuroepithelial cell hyperplasia, with a 2-fold increase in the number of pulmonary neuroendocrine cells in mice treated with doxycycline

• however normal respiratory epithelial cell differentiation and respiratory epithelial cell polarity

nervous system

increased solitary pulmonary neuroendocrine cell number ( J:146355 )

• pulmonary neuroepithelial cell hyperplasia, with a 2-fold increase in the number of pulmonary neuroendocrine cells in mice treated with doxycycline

• however normal respiratory epithelial cell differentiation and respiratory epithelial cell polarity

neoplasm

neoplasm ( J:146355 )

N • overt pulmonary tumors are not observed in doxycycline treated mice at 6 weeks of age

Genotype
MGI:5779422

cn11

• Allelic Composition: Gt(ROSA)26Sor^{tm1.1(rtTA2S*M2)Whsu}/Gt(ROSA)26Sor⁺; Ncstn^tm1.1Akli/Ncstn^tm1.1Akli; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129 * 129S6/SvEvTac * C57BL/6

neoplasm

increased urinary bladder carcinoma incidence ( J:227748 )

• doxycycline (dox) treated mice rapidly develop invasive urothelial cancer

• tumors of dox treated mice are high-grade urothelial carcinomas, grow mostly with a solid, non-glandular pattern and show blunt cellular atypia and focal glandular differentiation

• tumors invade the lamina and muscularis propria

• marker analysis indicates that tumors are related to human basal BLCA3 subtype

renal/urinary system

increased urinary bladder carcinoma incidence ( J:227748 )

• doxycycline (dox) treated mice rapidly develop invasive urothelial cancer

• tumors of dox treated mice are high-grade urothelial carcinomas, grow mostly with a solid, non-glandular pattern and show blunt cellular atypia and focal glandular differentiation

• tumors invade the lamina and muscularis propria

• marker analysis indicates that tumors are related to human basal BLCA3 subtype

hydronephrosis ( J:227748 )

• 12 of 18 mice develop unilateral or bilateral hydronephrosis as early as 2 weeks after dox treatment due to obstruction of the upper ureter by tumor masses

ureter obstruction ( J:227748 )

• due to bladder tumors in dox treated mice

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
urinary bladder cancer		DOID:11054	OMIM:109800	J:227748

Genotype
MGI:4942158

cn12

• Allelic Composition: Cebpa^tm1Dgt/Cebpa^tm1Dgt; Tg(SFTPC-rtTA)5Jaw/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129 * 129S6/SvEvTac * C57BL/6

mortality/aging

neonatal lethality, incomplete penetrance ( J:105593 )

• although born in Mendelian ratios, most mice exposed to doxycycline from conception die of respiratory failure at birth

respiratory system

abnormal pulmonary alveolus morphology ( J:105593 )

• doxycycline-exposed newborn mice show a reduction of airspace, sometimes obliterating the alveolar structure

abnormal pulmonary alveolus epithelial cell morphology ( J:105593 )

• doxycycline-exposed newborn mice display increased numbers of Ki-67-positive alveolar cells, indicating increased alveolar cell proliferation

• in addition, neonatal alveolar cells show significantly decreased numbers of TUNEL-positive cells, indicating reduced apoptosis

absent type I pneumocytes ( J:105593 )

• doxycycline-exposed newborn mice lack type I alveolar cells

abnormal type II pneumocyte morphology ( J:105593 )

• alveoli of doxycycline-exposed newborn mice are lined by immature cuboidal type II cells with a clear cytosol, round nuclei and high glycogen content, indicating a type II cell differentiation arrest

absent alveolar lamellar bodies ( J:105593 )

• immature type II alveolar cells of doxycycline-exposed newborn mice lack lamellar bodies

absent type II pneumocytes ( J:105593 )

• doxycycline-exposed newborn mice lack mature type II alveolar cells

increased pulmonary alveolus wall thickness ( J:105593 )

• doxycycline-exposed newborn mice display thicker alveolar walls due to marked cellular accumulation

respiratory distress ( J:105593 )

• 86% of mice exposed to doxycycline from conception show signs of respiratory distress within hours after birth

respiratory failure ( J:105593 )

• most mice exposed to doxycycline from conception to birth display respiratory failure

abnormal surfactant secretion ( J:105593 )

• doxycycline-exposed newborn mice show a marked loss of surfactant protein B (SP-B) by immunostaining

• mRNAs for SP-A and SP-D are significantly down-regulated

liver/biliary system

liver/biliary system phenotype ( J:105593 )

N • doxycycline-exposed mice have a normal liver architecture and show normal Cebpa mRNA levels in liver

hematopoietic system

hematopoietic system phenotype ( J:105593 )

N • doxycycline-exposed mice exhibit normal granulocytic differentiation in fetal liver and contain granulocytes in peripheral blood

Genotype
MGI:6376195

cn13

• Allelic Composition: Xbp1^tm2Glm/Xbp1^tm2Glm; Tg(Adipoq-rtTA)2Zvw/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129 * 129S6/SvEvTac * C57BL/6 * C57BL/6N

homeostasis/metabolism

abnormal nucleotide metabolism ( J:260830 )

• the 24 hour fasting-induced increase in plasma uridine that is seen in wild-type mice is reduced in doxycycline (Dox)-treated mutant mice

• however, mice do not show a reduced lipolysis response to the Beta3 adrenergic receptor agonist CL316,243

adipose tissue

increased body fat mass ( J:260830 )

• mice that are switched to a Dox high-fat diet at 69 weeks of age show a higher fat mass than controls 4 weeks after the diet switch

• however, Dox-treated mice fed a high-fat diet do not show a difference in body weight gain from wild-type mice fed the same diet

growth/size/body

increased body fat mass ( J:260830 )

• mice that are switched to a Dox high-fat diet at 69 weeks of age show a higher fat mass than controls 4 weeks after the diet switch

• however, Dox-treated mice fed a high-fat diet do not show a difference in body weight gain from wild-type mice fed the same diet

Genotype
MGI:4889055

cn14

• Allelic Composition: Foxm1^tm1Rhc/Foxm1^tm1Rhc; Tg(SFTPC-rtTA)5Jaw/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129 * 129X1/SvJ * C57BL/6

mortality/aging

neonatal lethality, incomplete penetrance ( J:142246 )

• 82% of mice treated with doxycycline from E7.5 to E14.5 die within the first 24 hrs after birth due to respiratory failure

respiratory system

respiratory system phenotype ( J:142246 )

N • mice treated with doxycycline during postnatal period P3-P30 show no differences in overall lung morphology or expression of epithelial marker proteins relative to control littermates

pulmonary vascular congestion ( J:142246 )

• 82% of mice treated with doxycycline from E7.5 to E14.5 display pulmonary congestion

abnormal lung development ( J:142246 )

• mice treated with doxycycline from E7.5 to E14.5 display delayed lung maturation, as shown by reduced lung sacculation and mesenchymal thickening prior to birth (E17.5 and E18.5)

• however, branching morphogenesis and proliferation of distal respiratory epithelial cells is normal at E15.5 and E18.5

• no vascular abnormalities are detected at E18.5, as shown by normal Pecam-1 staining

• differentiation of ciliated and Clara cells in conducting airways remains normal

abnormal lung saccule morphology ( J:142246 )

• mice treated with doxycycline from E7.5 to E14.5 display reduced lung sacculation prior to birth

• consistent with delayed lung maturation, peripheral lung tubules remain closed, unlike in control littermates

small lung saccule ( J:142246 )

• mice treated with doxycycline from E7.5 to E14.5 display smaller peripheral saccules at E17.5 and E18.5

thick lung-associated mesenchyme ( J:142246 )

• increased mesenchymal thickness prior to birth

abnormal pulmonary alveolus epithelial cell morphology ( J:142246 )

• mice treated with doxycycline from E7.5 to E14.5 show delayed differentiation of type I and type II epithelial cells

decreased type I pneumocyte number ( J:142246 )

• mice treated with doxycycline from E7.5 to E14.5 display reduced numbers of squamous type I epithelial cells

• however, type I epithelial cells appear ultrastructurally normal

abnormal type II pneumocyte morphology ( J:142246 )

small alveolar lamellar bodies ( J:142246 )

• mice treated with doxycycline from E7.5 to E14.5 show significantly smaller lamellar bodies in type II cells relative to control littermates

atelectasis ( J:142246 )

• mice treated with doxycycline from E7.5 to E14.5 display focal atelectasis

abnormal respiratory conducting tube morphology ( J:142246 )

• 82% of mice treated with doxycycline from E7.5 to E14.5 display pulmonary congestion, focal atelectasis, bronchial occlusion, and hyaline membranes lining terminal airways consistent with severe respiratory distress syndrome (RDS)

• ~18% of mice treated with doxycycline from E7.5 to E14.5 survive after birth and exhibit mild RDS with focal atelectasis

pulmonary hyaline membrane formation ( J:142246 )

• 82% of mice treated with doxycycline from E7.5 to E14.5 display hyaline membranes lining the terminal airways

respiratory distress ( J:142246 )

• 82% of mice treated with doxycycline from E7.5 to E14.5 display severe respiratory distress

respiratory failure ( J:142246 )

• 82% of mice treated with doxycycline from E7.5 to E14.5 die within the first 24 hrs after birth due to respiratory failure

decreased surfactant secretion ( J:142246 )

• mice treated with doxycycline from E7.5 to E14.5 show reduced pulmonary SP-A, SP-B, SP-C, and SP-D mRNA levels at E17.5 relative to control littermates

• SP-B mRNA is reduced to 40% of control values

cardiovascular system

pulmonary vascular congestion ( J:142246 )

• 82% of mice treated with doxycycline from E7.5 to E14.5 display pulmonary congestion

Genotype
MGI:5546509

cn15

• Allelic Composition: Ctnnb1^tm1Mmt/Ctnnb1⁺; Tg(Msx2-rtTA)885Lma/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129 * 129X1/SvJ * C57BL/6

craniofacial

abnormal craniofacial morphology ( J:202618 )

• mutants on a doxycycline diet exhibit craniofacial malformations

integument

alopecia ( J:202618 )

• mutants on a doxycycline diet exhibit alopecia

mortality/aging

premature death ( J:202618 )

• 35% of mutants on a doxycycline diet for at least 3 weeks starting at P25 die during the 12 weeks following doxycycline administration; males and females die at similar rates

renal/urinary system

abnormal urinary bladder morphology ( J:202618 )

• urothelia of males on the doxycycline diet is more severely affected than in females

• increase in urothelial basal cell proliferation is seen in mutants fed doxycycline

• bladders of males 5 weeks after doxycline treatment show a higher proliferation index than females at the same stage

increased urinary bladder carcinoma incidence ( J:202618 )

• 24% of the remaining surviving mutants on a doxycycline diet for at least 3 weeks starting at P25 exhibit tumors within the bladder lumen; 11 mutants have single tumor and 18 have multifoci tumors

• tumors in doxycline fed mutants resemble low-grade papillary urothelial carcinoma, exhibit polypoid structure, and the urothelium has lost its typical polarity and shows nuclear atypia, high mitogenic activity, and vascular infiltration

• however, no nuclear pleomorphism or muscle invasion is seen

• 45% of males on the doxycycline diet develop bladder tumors compared to 3% of females on the diet

• only 12.5% of castrated males after 3 months of doxycycline treatment develop luminal tumors and cell proliferation is 20% less than in noncastrated males

neoplasm

increased urinary bladder carcinoma incidence ( J:202618 )

• 24% of the remaining surviving mutants on a doxycycline diet for at least 3 weeks starting at P25 exhibit tumors within the bladder lumen; 11 mutants have single tumor and 18 have multifoci tumors

• tumors in doxycline fed mutants resemble low-grade papillary urothelial carcinoma, exhibit polypoid structure, and the urothelium has lost its typical polarity and shows nuclear atypia, high mitogenic activity, and vascular infiltration

• however, no nuclear pleomorphism or muscle invasion is seen

• 45% of males on the doxycycline diet develop bladder tumors compared to 3% of females on the diet

• only 12.5% of castrated males after 3 months of doxycycline treatment develop luminal tumors and cell proliferation is 20% less than in noncastrated males

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
urinary bladder cancer		DOID:11054	OMIM:109800	J:202618

Genotype
MGI:3809493

cn16

• Allelic Composition: Cebpa^tm1Gonz/Cebpa^tm1Gonz; Tg(SFTPC-rtTA)5Jaw/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129 * 129X1/SvJ * C57BL/6 * FVB/N

mortality/aging

neonatal lethality, complete penetrance ( J:106543 )

• mice die within 2 to 3 hours of birth

respiratory system

abnormal lung vasculature morphology ( J:106543 )

• capillary beds in lungs are immature

• however, vascular smooth muscle development is normal

pulmonary vascular congestion ( J:106543 )

• at birth, mice exhibit pulmonary congestion

abnormal lung saccule morphology ( J:106543 )

• between E16.5 and E18.5, mice exhibit reduced dilation of the saccules, thick mesenchyme and a lack of squamous type I cells unlike in wild-type mice

abnormal type I pneumocyte morphology ( J:106543 )

• type I cell maturation is disrupted

absent type I pneumocytes ( J:106543 )

• mature type I cells are absent

abnormal type II pneumocyte morphology ( J:106543 )

• type II cell maturation is disrupted and cells lack stored pulmonary surfactant

atelectasis ( J:106543 )

• at birth

respiratory distress ( J:106543 )

• at birth

abnormal surfactant secretion ( J:106543 )

• mice produce less surfactant protein than wild-type mice

cardiovascular system

abnormal lung vasculature morphology ( J:106543 )

• capillary beds in lungs are immature

• however, vascular smooth muscle development is normal

pulmonary vascular congestion ( J:106543 )

• at birth, mice exhibit pulmonary congestion

Genotype
MGI:5512989

cn17

• Allelic Composition: Notch1^tm2Rko/Notch1^tm2Rko; Tg(KRT14-rtTA)F42Efu/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129 * 129X1/SvJ * C57BL/6 * FVB/N

vision/eye

Meibomian gland degeneration ( J:194073 )

• mutants treated with doxycycline from P1 to P16 show degeneration of ocular glands, including lacrimal and Meibomian glands

lacrimal gland degeneration ( J:194073 )

• mutants treated with doxycycline from P1 to P16 show degeneration of ocular glands, including lacrimal and Meibomian glands

decreased conjunctiva goblet cell number ( J:194073 )

• mutants treated with doxycycline from P1 to P16 exhibit loss of conjunctival goblet cells

dry eyes ( J:194073 )

• mutants treated with doxycycline from P1 to P16 have poor tear volume

endocrine/exocrine glands

Meibomian gland degeneration ( J:194073 )

• mutants treated with doxycycline from P1 to P16 show degeneration of ocular glands, including lacrimal and Meibomian glands

lacrimal gland degeneration ( J:194073 )

• mutants treated with doxycycline from P1 to P16 show degeneration of ocular glands, including lacrimal and Meibomian glands

integument

Meibomian gland degeneration ( J:194073 )

• mutants treated with doxycycline from P1 to P16 show degeneration of ocular glands, including lacrimal and Meibomian glands

alopecia ( J:194073 )

• mutants treated with doxycycline from P1 to P16 show hair loss on the skin and eyelids

Genotype
MGI:3806650

cn18

• Allelic Composition: Klf5^tm1Jaw/Klf5^tm1Jaw; Tg(SFTPC-rtTA)5Jaw/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129 * C57BL/6

mortality/aging

neonatal lethality, complete penetrance ( J:138576 )

• doxycycline treated mice die shortly after birth due to respiratory distress

respiratory system

abnormal lung development ( J:138576 )

• in doxycycline treated mice, pulmonary mesenchyme is thickened and blood vessels are not found in close proximity to epithelial cells unlike in wild-type mice

• in doxycycline treated mice, lung maturation during saccule development is inhibited

• however, at E15.5 lung development is normal

abnormal lung saccule morphology ( J:138576 )

• at birth, doxycycline treated mice exhibit hypercellular alveolar saccules without the dilated peripheral saccules found in wild-type mice

• saccules in doxycycline treated mice are thickened compared to in wild-type mice

thick lung-associated mesenchyme ( J:138576 )

• doxycycline treated mice exhibit thickened lung mesenchyme

abnormal pulmonary alveolus morphology ( J:138576 )

• at birth, doxycycline treated mice exhibit a decrease in alveolar luminal area compared to wild-type mice

abnormal type I pneumocyte morphology ( J:138576 )

• at birth, doxycycline treated mice exhibit a decrease in squamous epithelial cells compared to in wild-type mice indicating a lack of alveolar type I cell differentiation

• however, pulmonary epithelial cell proliferation following dooxycycline treatment is normal

decreased type I pneumocyte number ( J:138576 )

• at birth, doxycycline treated mice exhibit a decrease in squamous epithelial cells compared to in wild-type mice

abnormal type II pneumocyte morphology ( J:138576 )

• in doxycycline treated mice, type II cells lack lamellar structures found in wild-type cells

absent alveolar lamellar bodies ( J:138576 )

respiratory distress ( J:138576 )

• doxycycline treated mice die shortly after birth due to respiratory distress

abnormal surfactant secretion ( J:138576 )

• unlike in wild-type mice, no surfactant secretion or Sftpb protein is detected in doxycycline treated mice

Genotype
MGI:3833133

cn19

• Allelic Composition: Itga3^tm1Hap/Itga3^tm1Hap; Tg(SFTPC-rtTA)5Jaw/?; Tg(tetO-cre)1Jaw/?
• Genetic Background: involves: 129 * C57BL/6

Itga3^tm1Hap/Itga3^tm1Hap Tg(SFTPC-rtTA)5Jaw/? Tg(tetO-cre)1Jaw/? mice exhibit increased bronchoalveolar lavage cellularity at baseline and after bleomycin injury

respiratory system

pulmonary hyperplasia ( J:144703 )

• cellularity in BAL fluid is almost double that of controls in mice with cre induction

• increase in cellularity is also found after bleomycin injury of the lung

increased type II pneumocyte number ( J:144703 )

• there is about a 2-fold increase in the number of type II alveolar cells present in the lungs of mice treated with doxycycline

thick pulmonary interalveolar septum ( J:144703 )

• alveolar septa are thickened with increased deposition of collagen IV in mice with cre induction

pulmonary fibrosis ( J:144703 )

• bleomycin injury of the lungs leads to less fibrosis three weeks later due to impaired myofibroblast accumulation and reduced type I collagen response

• the number of myofibroblast per field is 4-5 fold less than in controls after bleomycin injury

decreased lung compliance ( J:144703 )

• there is a trend towards less compliance in these mice after bleomycin injury than in controls

growth/size/body

pulmonary hyperplasia ( J:144703 )

• cellularity in BAL fluid is almost double that of controls in mice with cre induction

• increase in cellularity is also found after bleomycin injury of the lung

Genotype
MGI:3833134

cn20

• Allelic Composition: Itga3^tm1Hap/Itga3^tm1Hap; Tg(CAG-Bgeo/GFP)21Lbe/?; Tg(SFTPC-rtTA)5Jaw/?; Tg(tetO-cre)1Jaw/?
• Genetic Background: involves: 129 * C57BL/6

respiratory system

abnormal pulmonary alveolus epithelial cell morphology ( J:144703 )

• epithelial to mesenchymal transition results from bleomycin-mediated injury of the lung

• only 1.4% of GFP⁺, epithelium derived cells express mesenchyme markers 17 days after bleomycin injury compared to 7.0% in controls

Genotype
MGI:5688535

cn21

• Allelic Composition: Tg(CAG-cat,-Il18)#Thos/0; Tg(SFTPC-rtTA)5Jaw/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129 * C57BL/6

immune system

increased interferon-gamma secretion ( J:147547 )

• mice administered doxycycline (Dox) exhibit an increase in IFN-gamma production in the lungs

interstitial pneumonia ( J:147547 )

• mice treated with Dox show pulmonary inflammation, with infiltration of mononuclear cells in the alveolar wall and general interstitium, indicating interstitial pneumonia

• however, mice treated with Dox do not exhibit emphysema, swelled alveolar macrophages, hyaline membranes, or proteinaceous debris, and show no evidence of increased lung volumes or cardiomegaly

respiratory system

interstitial pneumonia ( J:147547 )

• mice treated with Dox show pulmonary inflammation, with infiltration of mononuclear cells in the alveolar wall and general interstitium, indicating interstitial pneumonia

• however, mice treated with Dox do not exhibit emphysema, swelled alveolar macrophages, hyaline membranes, or proteinaceous debris, and show no evidence of increased lung volumes or cardiomegaly

abnormal pulmonary alveolus morphology ( J:147547 )

• mean alveolar chord length is lower than in wild-type mice

Genotype
MGI:4418250

cn22

• Allelic Composition: Gt(ROSA)26Sor^{tm1(rtTA,EGFP)Nagy}/Gt(ROSA)26Sor⁺; Rbpj^tm1Hon/Rbpj^tm1Hon; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129 * C57BL/6

mortality/aging

neonatal lethality, complete penetrance ( J:155893 )

• doxycycline-treated mice die shortly after birth

respiratory system

abnormal lung development ( J:155893 )

• at E18.5, myofibroblasts in the lungs of doxycycline-treated mice exhibit reduced differentiation, as determined by sma+ expression, compared to in wild-type mice

Genotype
MGI:4938179

cn23

• Allelic Composition: Vegfa^tm2Gne/Vegfa^tm2Gne; Tg(SFTPC-rtTA)5Jaw/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129 * C57BL/6

mortality/aging

neonatal lethality, complete penetrance ( J:124125 )

• newborn mice exposed to doxycycline from E6.5 develop respiratory distress and die within 1-2 hrs of birth

respiratory system

abnormal lung vasculature morphology ( J:124125 )

• at E18.5, doxycycline-exposed mice display an almost complete absence of pulmonary capillaries associated with defective primary septation during distal lung morphogenesis

• at E18.5, lung saccular walls without capillaries exhibit no septae while septae containing a residual (single) capillary or disorganized capillaries are malformed and show abnormal shapes with an expanded mesenchyme

decreased pulmonary endothelial cell surface ( J:124125 )

• at E18.5, doxycycline-exposed mice exhibit significantly reduced pulmonary endothelial cell development relative to controls

abnormal pulmonary circulation ( J:124125 )

• at birth, doxycycline-exposed mice display white lungs, indicating a lack of pulmonary circulation

abnormal lung development ( J:124125 )

• mice exposed to doxycycline from E6.5 display defective distal lung saccular development due to reduced primary septation; first seen at E16.5 when terminal tubules appear more dilated

• defective distal airspace morphogenesis is also noted when mice are exposed to doxycycline from E14.5 to birth

• impaired primary septation is likely due to reduced hepatocyte growth factor (Hgf) expression

decreased mesenchymal cell proliferation involved in lung development ( J:124125 )

• at E18.5, doxycycline-exposed mice display a significant reduction in proliferating (BrdU+) lung mesenchymal cells relative to controls

abnormal lung saccule morphology ( J:124125 )

• at E18.5, doxycycline-exposed mice display significantly dilated distal airspaces with fewer subdivisions by primary septae than controls

• at E18.5, doxycycline-exposed mice display a mosaic pattern of normal and abnormal septae that is dependent on the residual capillary structures

• at birth, ventilation of doxycycline-exposed lungs results in marked dilation of terminal airspaces and thinning of saccular walls

abnormal lung epithelium morphology ( J:124125 )

• at E18.5, doxycycline-exposed mice display a 65% reduction in proliferating (BrdU+) lung epithelial cells relative to controls

• however, epithelial cell survival and proximal-distal patterning of epithelial cell differentiation remain normal

abnormal pulmonary acinus morphology ( J:124125 )

• at E16.5 and E17.5, doxycycline-exposed mice display abnormal distal acini and more dilated distal tubules than controls

pale lung ( J:124125 )

• at birth, doxycycline-exposed mice display white lungs

respiratory distress ( J:124125 )

• newborn mice exposed to doxycycline from E6.5 develop respiratory distress and die within 1-2 hrs of birth

cardiovascular system

abnormal lung vasculature morphology ( J:124125 )

• at E18.5, doxycycline-exposed mice display an almost complete absence of pulmonary capillaries associated with defective primary septation during distal lung morphogenesis

• at E18.5, lung saccular walls without capillaries exhibit no septae while septae containing a residual (single) capillary or disorganized capillaries are malformed and show abnormal shapes with an expanded mesenchyme

decreased pulmonary endothelial cell surface ( J:124125 )

• at E18.5, doxycycline-exposed mice exhibit significantly reduced pulmonary endothelial cell development relative to controls

decreased angiogenesis ( J:124125 )

• at E18.5, doxycycline-exposed mice display significantly reduced pulmonary capillary angiogenesis associated with defective primary septation during distal lung morphogenesis

abnormal pulmonary circulation ( J:124125 )

• at birth, doxycycline-exposed mice display white lungs, indicating a lack of pulmonary circulation

cellular

decreased mesenchymal cell proliferation involved in lung development ( J:124125 )

• at E18.5, doxycycline-exposed mice display a significant reduction in proliferating (BrdU+) lung mesenchymal cells relative to controls

Genotype
MGI:4938194

cn24

• Allelic Composition: Vegfa^tm2Gne/Vegfa⁺; Tg(SFTPC-rtTA)5Jaw/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129 * C57BL/6

respiratory system

decreased pulmonary endothelial cell surface ( J:124125 )

• at E18.5, doxycycline-exposed mice exhibit a reduction in pulmonary endothelial cell development that is intermediate between those of wild-type controls and those carrying two Vegfa^tm2Gne alleles

abnormal pulmonary circulation ( J:124125 )

• newborn mice exposed to doxycycline from E6.5 display pale lungs, indicating reduced pulmonary circulation

abnormal lung development ( J:124125 )

• mice exposed to doxycycline from E6.5 display defective distal lung saccular development due to moderately reduced primary septation

abnormal lung saccule morphology ( J:124125 )

• at E18.5, doxycycline-exposed mice display dilated distal airspaces of a size that is intermediate between those of wild-type controls and those carrying two Vegfa^tm2Gne alleles

• the mean linear intercept, a reflection of airspace size and hence an indirect measure of septation incidence, is inversely related to the Vegfa gene dosage

pale lung ( J:124125 )

• newborn mice exposed to doxycycline from E6.5 display pale lungs

cardiovascular system

decreased pulmonary endothelial cell surface ( J:124125 )

• at E18.5, doxycycline-exposed mice exhibit a reduction in pulmonary endothelial cell development that is intermediate between those of wild-type controls and those carrying two Vegfa^tm2Gne alleles

abnormal pulmonary circulation ( J:124125 )

• newborn mice exposed to doxycycline from E6.5 display pale lungs, indicating reduced pulmonary circulation

Genotype
MGI:5613585

cn25

• Allelic Composition: Gt(ROSA)26Sor^{tm4(Wnt7b)Flng}/Gt(ROSA)26Sor⁺; Tg(Runx2-rtTA*M2)#Flng/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129 * C57BL/6

skeleton

abnormal bone structure ( J:208766 )

decreased osteoclast cell number ( J:208766 )

• after doxycycline treatment

increased bone mineral density ( J:208766 )

• in the long bones after doxycycline treatment

increased trabecular bone volume ( J:208766 )

• proximal tibial trabecular bone volume/total volume is increased 6.6 fold at 2 months of age after doxycycline treatment

increased osteoblast cell number ( J:208766 )

• markedly increased after doxycycline treatment

increased trabecular bone mass ( J:208766 )

• marked increase in the trabecular bone mass in both primary and secondary ossification centers

increased bone ossification ( J:208766 )

• increased bone formation after doxycycline treatment

immune system

decreased osteoclast cell number ( J:208766 )

• after doxycycline treatment

hematopoietic system

decreased osteoclast cell number ( J:208766 )

• after doxycycline treatment

Genotype
MGI:6790452

cn26

• Allelic Composition: Eif4b^tm1.1Smoc/Eif4b^tm1.1Smoc; Tg(SFTPC-rtTA)5Jaw/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129 * C57BL/6

immune system

increased susceptibility to Orthomyxoviridae infection ( J:311140 )

• doxycycline-treated mice show increased susceptibility to influenza A virus infection, showing increased influenza A replication

Genotype
MGI:5543893

cn27

• Allelic Composition: Elavl1^tm1Lix/Elavl1^tm1Lix; Tg(Scgb1a1-rtTA)2Jaw/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129 * C57BL/6

immune system

decreased inflammatory response ( J:204952 )

• reduced pulmonary inflammation in mice treated with doxycycline and intranasal rIL17

lung inflammation ( J:204952 )

• reduced pulmonary inflammation in mice treated with doxycycline and intranasal rIL17

respiratory system

lung inflammation ( J:204952 )

• reduced pulmonary inflammation in mice treated with doxycycline and intranasal rIL17

Genotype
MGI:6790454

cn28

• Allelic Composition: Eif4b^tm1.1Smoc/Eif4b⁺; Tg(SFTPC-rtTA)5Jaw/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129 * C57BL/6

immune system

increased susceptibility to Riboviria infection ( J:311140 )

• doxycycline-treated mice show increased susceptibility to pseudorabies virus infection, showing increased pseudorabies virus-gE in lungs and brains

Genotype
MGI:6376235

cn29

• Allelic Composition: Cad^{tm1c(KOMP)Wtsi}/Cad^{tm1c(KOMP)Wtsi}; Tg(Adipoq-rtTA)2Zvw/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129 * C57BL/6 * C57BL/6N
• Cell Lines: EPD0282_2_F10

adipose tissue

decreased white fat cell size ( J:260830 )

• mice show a moderate size reduction of adipocytes in subcutaneous white adipose tissue (sWAT) when fed a Dox-containing diet

• however, no differences in epididymal white adipose tissue (eWAT) or interscapular brown adipose tissue (BAT) adipocyte size is seen

growth/size/body

growth/size/body region phenotype ( J:260830 )

N • mice do not show differences in bodyweight gain from wild-type mice when treated with doxycycline (Dox)

Genotype
MGI:6392317

cn30

• Allelic Composition: Tulp3^{tm1c(EUCOMM)Hmgu}/Tulp3^{tm1c(EUCOMM)Hmgu}; Tg(Pax8-rtTA2S*M2)1Koes/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129 * C57BL/6 * C57BL/6N * DBA * SJL

renal/urinary system

kidney cyst ( J:284006 )

• mice treated with Dox at P28 for 2 weeks and analyzed at 41-42 weeks of age show slow development of kidney cysts

• mice treated with Dox at P0 and analyzed at P14 show a modest kidney phenotype, with a few cysts

• however, blood urea nitrogen levels are normal in Dox treated mice

dilated renal tubule ( J:284006 )

• mice treated with doxycycline (Dox) at P0 and analyzed at P14 show a modest kidney phenotype, with mild tubule dilatations

growth/size/body

kidney cyst ( J:284006 )

• mice treated with Dox at P28 for 2 weeks and analyzed at 41-42 weeks of age show slow development of kidney cysts

• mice treated with Dox at P0 and analyzed at P14 show a modest kidney phenotype, with a few cysts

• however, blood urea nitrogen levels are normal in Dox treated mice

Genotype
MGI:6376231

cn31

• Allelic Composition: Cad^{tm1c(KOMP)Wtsi}/Cad^{tm1c(KOMP)Wtsi}; Tg(Adipoq-rtTA)2Zvw/0; Tg(tetO-cre)1Jaw/0; Tg(tetO-Xbp1_is)#Pesch/0
• Genetic Background: involves: 129 * C57BL/6 * C57BL/6N * FVB/N
• Cell Lines: EPD0282_2_F10

growth/size/body

weight loss ( J:260830 )

• mice continue to increase their body weight when switched to a doxycycline (Dox)-containing diet, although not at the same extent as wild-type mice thus showing a partial reversal of weight loss

adipose tissue

adipose tissue phenotype ( J:260830 )

N • size of adipocytes is epididymal white adipose tissue (eWAT), subcutaneous white adipose tissue (sWAT), and in interscapular brown adipose tissue (BAT)is normal in Dox-treated mice

N • adipose tissue uridine content is not increased and thus rescued in Dox-treated mice compared to Tg(tetO-Xbp1_is)#Pesch/0 Tg(Adipoq-rtTA)2Zvw/0 mice

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:260830 )

N • adipose tissue uridine content is not increased and thus rescued in Dox-treated mice compared to Tg(tetO-Xbp1_is)#Pesch/0 Tg(Adipoq-rtTA)2Zvw/0 mice

Genotype
MGI:5512988

cn32

• Allelic Composition: Gt(ROSA)26Sor^{tm1(MAML1)Wsp}/Gt(ROSA)26Sor⁺; Tg(KRT14-rtTA)F42Efu/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129 * C57BL/6 * FVB

vision/eye

conjunctivitis ( J:194073 )

• CD45+ leukocyte infiltration is seen in the sub-conjunctival stroma 3-4 days after eyelid opening, at P16, of pups treated with doxycycline

abnormal eye morphology ( J:194073 )

• epithelial cells of the ocular surface of pups treated with doxycycline (via nursing moms) are hyperplastic and aberrantly desquamated from the conjunctiva

cornea vascularization ( J:194073 )

• pulse doxycycline induction from P0 to P16 results in mutants with severe ulceration and neovascularization in the cornea, even after 180 days post-doxycycline induction

abnormal conjunctival epithelium morphology ( J:194073 )

• the aberrantly desquamated cells within the conjunctival sac are composed of conjunctival epithelial cells and basal cells of stratified epithelia but not corneal epithelial cells, indicating aberrant conjunctival, but not corneal, epithelial cell desquamation

• conjunctival epithelia from pups treated with doxycycline (via nursing moms) exhibit an increase in cell proliferation

abnormal conjunctiva goblet cell differentiation ( J:194073 )

• pups treated with doxycycline (via nursing moms) do not show signs of goblet cell differentiation from the conjunctival epithelium at P9 or P16 unlike controls

decreased conjunctiva goblet cell number ( J:194073 )

• adult mice administered doxycycline at P90 exhibit loss of goblet cells from the conjunctiva and cellular debris in the conjunctival sac

abnormal conjunctival sac morphology ( J:194073 )

• pups from nursing moms administered doxycycline do not exhibit clear conjunctival sacs at P9 as in wild-type pups and instead have a mass of cell debris that is abnormally present in the conjunctival sac, indicating early ocular surface morphogenesis alterations

• adult mice administered doxycycline at P90 exhibit cellular debris in the conjunctival sac

abnormal cornea epithelium morphology ( J:194073 )

• pups treated with doxycycline exhibit epidermal metaplasia of corneal epithelium at P16

cornea ulcer ( J:194073 )

• pulse doxycycline induction from P0 to P16 results in mutants with severe ulceration and neovascularization in the cornea, even after 180 days post-doxycycline induction

cardiovascular system

cornea vascularization ( J:194073 )

• pulse doxycycline induction from P0 to P16 results in mutants with severe ulceration and neovascularization in the cornea, even after 180 days post-doxycycline induction

immune system

conjunctivitis ( J:194073 )

• CD45+ leukocyte infiltration is seen in the sub-conjunctival stroma 3-4 days after eyelid opening, at P16, of pups treated with doxycycline

integument

alopecia ( J:194073 )

• adult mice administered doxycycline at P90, exhibit hair loss one month after doxycycline induction, with random alopecia on the body, including the eyelid within 3 months

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
keratoconjunctivitis sicca		DOID:12895		J:194073

Genotype
MGI:5571468

cn33

• Allelic Composition: Adam17^tm1.1Wesh/Adam17^tm1.1Wesh; Tg(Scgb1a1-rtTA)2Jaw/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129 * C57BL/6 * FVB/N

mortality/aging

mortality/aging ( J:210193 )

N • doxycycline-treated mice exhibit normal neonatal survival

respiratory system

abnormal lung vasculature morphology ( J:210193 )

• reduced pulmonary capillary formation in doxycycline-treated mice

abnormal lung saccule morphology ( J:210193 )

• at E18.5, doxycycline-treated mice exhibit reduced terminal sacs and thickened surrounding mesenchyme in the peripheral lung compared with control mice

• larger but fewer sacs at P1 in doxycycline-treated mice

• however, morphology at P14 and P30 is normal

thick lung-associated mesenchyme ( J:210193 )

• at E18.5 in doxycycline-treated mice

abnormal lung epithelium morphology ( J:210193 )

• impaired epithelial cell differentiation in doxycycline-treated mice

cellular

decreased cell proliferation ( J:210193 )

• at P1, but not P30, in the lungs of doxycycline-treated mice

cardiovascular system

abnormal lung vasculature morphology ( J:210193 )

• reduced pulmonary capillary formation in doxycycline-treated mice

Genotype
MGI:5301912

cn34

• Allelic Composition: Tg(Scgb1a1-rtTA)2Jaw/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129 * C57BL/6 * FVB/N

mortality/aging

mortality/aging ( J:179352 )

N • doxycycline-treated mice do not exhibit perinatal toxicity

respiratory system

respiratory system phenotype ( J:179352 )

N • doxycycline-treated mice do not exhibit lung pathology or dysfunction

N • doxycycline-treated mice exhibit minimal focal airspace enlargement unlike Tg(Scgb1a1-rtTA)1Jaw mice

Genotype
MGI:5431582

cn35

• Allelic Composition: Drosha^tm1Ghan/Drosha^tm1Ghan; Tg(KRT5-rtTA)1Glk/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129 * C57BL/6 * FVB/N

integument

abnormal hair follicle bulge morphology ( J:183487 )

• at P50 doxycycline-treated mice exhibit loss of bulge stem cells unlike in control mice

• however, bulge stem cells are present at P20 and P22

growth/size/body

decreased body size ( J:183487 )

• in doxycycline-treated mice

Genotype
MGI:5613965

cn36

• Allelic Composition: Angpt1^tm1.1Seq/Angpt1^tm1.1Seq; Angpt2^{tm1c(KOMP)Seq}/Angpt2^{tm1c(KOMP)Seq}; Gt(ROSA)26Sor^{tm1(rtTA,EGFP)Nagy}/?; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129 * C57BL/6NCr

cardiovascular system

cornea vascularization ( J:217296 )

• capillary loops extend into the cornea

vision/eye

abnormal eye morphology ( J:217296 )

• in mice exposed to deoxycycline treatment at E16.5

abnormal anterior eye segment morphology ( J:217296 )

absent Schlemm's canal ( J:217296 )

abnormal cornea morphology ( J:217296 )

• lymphatic vasculature develops in the corneal limbus

cornea vascularization ( J:217296 )

• capillary loops extend into the cornea

increased cornea size ( J:217296 )

• enlarged

increased eye anterior chamber depth ( J:217296 )

• increased anterior chamber depth

buphthalmos ( J:217296 )

• eyes begin to protrude by 21 to 28 days of age

• difficulty closing eyelids by 8 weeks of age

abnormal retina layer morphology ( J:217296 )

• reduced thickness of retinal cell layer

thin retina ganglion layer ( J:217296 )

thin retina inner nuclear layer ( J:217296 )

abnormal retina nerve fiber layer morphology ( J:217296 )

• reduced thickness

thin retina outer nuclear layer ( J:217296 )

• becoming worse toward periphery

abnormal eye physiology ( J:217296 )

• in mice exposed to deoxycycline treatment at E16.5

abnormal intraocular pressure ( J:217296 )

• elevated

decreased visual acuity ( J:217296 )

• severely impaired vision

immune system

abnormal lymphatic vessel morphology ( J:217296 )

• lymphatic vessels are sparse in the dermis of the ear

• abnormal branching of lymphatic vessels

Genotype
MGI:5613966

cn37

• Allelic Composition: Tek^tm1.1Vlcg/Tek^tm1.1Vlcg; Gt(ROSA)26Sor^{tm1(rtTA,EGFP)Nagy}/?; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129 * C57BL/6NCr

vision/eye

abnormal anterior eye segment morphology ( J:217296 )

• in mice exposed to deoxycycline treatment at E16.5

increased cornea size ( J:217296 )

• enlarged

increased eye anterior chamber depth ( J:217296 )

• increased anterior chamber depth

buphthalmos ( J:217296 )

• eyes begin to protrude by 21 to 28 days of age in mice exposed to deoxycycline treatment at E16.5

• difficulty closing eyelids by 8 weeks of age

Genotype
MGI:5581951

cn38

• Allelic Composition: Ctnnb1^tm2Kem/Ctnnb1^tm2Kem; Pparg^{tm1.1(tTA)Jmgr}/Pparg⁺; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129P2/OlaHsd * 129S1/Sv * 129X1/SvJ * C57BL/6

skeleton

skeleton phenotype ( J:178340 )

N • mice exhibit normal bone formation and osteoblast surface/numbers

decreased osteoclast cell number ( J:178340 )

abnormal osteoclast physiology ( J:178340 )

• decreased proliferation of osteoclast precursors

increased bone volume ( J:178340 )

• at 6 months

increased compact bone volume ( J:178340 )

• at 6 months

abnormal trabecular bone morphology ( J:178340 )

• more trabecular bone and bone surface at 6 months

increased trabecular bone volume ( J:178340 )

• at 6 months

increased bone trabecula number ( J:178340 )

• with reduced spacing at 6 months

increased trabecular bone thickness ( J:178340 )

• at 6 months

osteopetrosis ( J:178340 )

decreased bone resorption ( J:178340 )

hematopoietic system

extramedullary hematopoiesis ( J:178340 )

decreased osteoclast cell number ( J:178340 )

abnormal osteoclast physiology ( J:178340 )

• decreased proliferation of osteoclast precursors

immune system

decreased osteoclast cell number ( J:178340 )

abnormal osteoclast physiology ( J:178340 )

• decreased proliferation of osteoclast precursors

Genotype
MGI:5581952

cn39

• Allelic Composition: Ctnnb1^tm2Kem/Ctnnb1⁺; Pparg^{tm1.1(tTA)Jmgr}/Pparg⁺; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129P2/OlaHsd * 129S1/Sv * 129X1/SvJ * C57BL/6

skeleton

skeleton phenotype ( J:178340 )

N • doxycycline-treated mice exhibit normal numbers of osteoblasts, bone formation and bone mineral apposition rates

increased osteoclast cell number ( J:178340 )

• in doxycycline-treated mice

abnormal osteoclast physiology ( J:178340 )

• doxycycline-treated bone marrow cultures exhibit reduced osteoclast precursor proliferation compared with control cultures

abnormal trabecular bone morphology ( J:178340 )

• decreased bone surface in doxycycline-treated mice

decreased trabecular bone volume ( J:178340 )

• trabecular, cortical and total in doxycycline-treated mice

decreased bone trabecula number ( J:178340 )

• with increased spacing in doxycycline-treated mice

decreased trabecular bone mass ( J:178340 )

• in doxycycline-treated mice

decreased trabecular bone thickness ( J:178340 )

• in doxycycline-treated mice

osteoporosis ( J:178340 )

• in doxycycline-treated mice

increased bone resorption ( J:178340 )

• in doxycycline-treated mice

hematopoietic system

increased osteoclast cell number ( J:178340 )

• in doxycycline-treated mice

abnormal osteoclast physiology ( J:178340 )

• doxycycline-treated bone marrow cultures exhibit reduced osteoclast precursor proliferation compared with control cultures

immune system

increased osteoclast cell number ( J:178340 )

• in doxycycline-treated mice

abnormal osteoclast physiology ( J:178340 )

• doxycycline-treated bone marrow cultures exhibit reduced osteoclast precursor proliferation compared with control cultures

Genotype
MGI:5581950

cn40

• Allelic Composition: Ctnnb1^tm2Kem/Ctnnb1^tm2Kem; Pparg^{tm1.1(tTA)Jmgr}/Pparg⁺; Tg(tetO-cre)1Jaw/0; Tg(tetO-HIST1H2BJ/GFP)47Efu/0
• Genetic Background: involves: 129P2/OlaHsd * 129S1/Sv * 129X1/SvJ * C57BL/6 * CD-1

skeleton

abnormal osteoclast differentiation ( J:178340 )

• cultured bone marrow cells contain fewer osteoclast precursors compared with control mice

hematopoietic system

abnormal osteoclast differentiation ( J:178340 )

• cultured bone marrow cells contain fewer osteoclast precursors compared with control mice

cellular

abnormal osteoclast differentiation ( J:178340 )

• cultured bone marrow cells contain fewer osteoclast precursors compared with control mice

immune system

abnormal osteoclast differentiation ( J:178340 )

• cultured bone marrow cells contain fewer osteoclast precursors compared with control mice

Genotype
MGI:5581956

cn41

• Allelic Composition: Ctnnb1^tm1Mmt/Ctnnb1⁺; Pparg^{tm1.1(tTA)Jmgr}/Pparg⁺; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129P2/OlaHsd * 129X1/SvJ * C57BL/6

skeleton

skeleton phenotype ( J:178340 )

N • doxycycline-treated mice exhibit normal bone formation and numbers of osteoblasts

abnormal osteoclast differentiation ( J:178340 )

• impaired in doxycycline-treated mice

decreased osteoclast cell number ( J:178340 )

• in doxycycline-treated mice

increased bone volume ( J:178340 )

• as early as P15 in doxycycline-treated mice

• 27-fold from 10 months of age in doxycycline-treated mice

increased compact bone volume ( J:178340 )

• in doxycycline-treated mice

abnormal trabecular bone morphology ( J:178340 )

• 4.6-fold increase in trabecular bone surface and a smaller bone surface to bone volume in doxycycline-treated mice

increased trabecular bone volume ( J:178340 )

• trabecular, cortical and total volume as early as P15 in doxycycline-treated mice

increased bone trabecula number ( J:178340 )

• 3.6-fold with reduced trabecular separation in doxycycline-treated mice

increased trabecular bone thickness ( J:178340 )

• 8.5-fold in doxycycline-treated mice

osteopetrosis ( J:178340 )

• severe in doxycycline-treated mice

• in mice following adult onset activation with doxycycline

decreased bone resorption ( J:178340 )

• in doxycycline-treated mice

hematopoietic system

abnormal osteoclast differentiation ( J:178340 )

• impaired in doxycycline-treated mice

extramedullary hematopoiesis ( J:178340 )

• in doxycycline-treated mice

decreased bone marrow cell number ( J:178340 )

• at 4 months in doxycycline-treated mice

absent bone marrow cell ( J:178340 )

• at 10 months in doxycycline-treated mice

decreased osteoclast cell number ( J:178340 )

• in doxycycline-treated mice

increased splenocyte number ( J:178340 )

• gradual in doxycycline-treated mice

cellular

abnormal osteoclast differentiation ( J:178340 )

• impaired in doxycycline-treated mice

immune system

abnormal osteoclast differentiation ( J:178340 )

• impaired in doxycycline-treated mice

decreased osteoclast cell number ( J:178340 )

• in doxycycline-treated mice

increased splenocyte number ( J:178340 )

• gradual in doxycycline-treated mice

Genotype
MGI:5431584

cn42

• Allelic Composition: Drosha^tm1Litt/Drosha^tm1Litt; Tg(KRT5-rtTA)1Glk/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6 * FVB/N

integument

integument phenotype ( J:183487 )

N • doxycycline-treated mice retain hair follicle stem cells in early telogen and anagen

abnormal coat/ hair morphology ( J:183487 )

• hair phenotype in doxycycline-treated mice appears more slowly than in Dicer1^tm1Smr/Dicer1^tm1Smr Tg(KRT5-rtTA)1Glk Tg(tetO-cre)1Jaw mice

abnormal hair growth ( J:183487 )

• failure of hair regrowth in doxycycline-treated mice

• failure of regression at P20 in doxycycline-treated mice and remained in an abnormal growth phase

• following hair plucking, doxycycline-treated mice fail to sustain hair growth unlike control mice

alopecia ( J:183487 )

• after P14 in doxycycline-treated mice

waved hair ( J:183487 )

• external hair becomes wavy between P12 and P14 in doxycycline-treated mice

abnormal hair shaft morphology ( J:183487 )

• in doxycycline-treated mice likely due to matrix cell apoptosis

abnormal hair follicle morphology ( J:183487 )

• at P17 in doxycycline-treated mice after degradation begins

abnormal hair follicle inner root sheath morphology ( J:183487 )

• fewer differentiation cell in doxycycline-treated mice following plucking-induced anagen initiation

hair follicle degeneration ( J:183487 )

• with extrusion of abnormally keratinized cellular material in doxycycline-treated mice

small hair follicles ( J:183487 )

• in doxycycline-treated mice following plucking-induced anagen initiation

abnormal hair cycle catagen phase ( J:183487 )

• failure of catagen in doxycycline-treated mice

abnormal hair follicle regression ( J:183487 )

• failure of regression at P20 in doxycycline-treated mice

epidermal hyperplasia ( J:183487 )

• by P20, doxycycline-treated mice exhibit thickened interfollicular epidermis compared with control mice

dry skin ( J:183487 )

• mice treated with doxycycline exhibit a temporary phenotype of dry scaly skin that is resolved in an anterior-posterior direction

scaly skin ( J:183487 )

• mice treated with doxycycline exhibit a temporary phenotype of dry scaly skin that is resolved in an anterior-posterior direction

abnormal skin physiology ( J:183487 )

cellular

increased apoptosis ( J:183487 )

• doxycycline-treated mice exhibit matrix cell apoptosis with DNA damage response unlike in control mice

growth/size/body

decreased body size ( J:183487 )

• in doxycycline-treated mice

Genotype
MGI:4941006

cn43

• Allelic Composition: Nedd4l^tm1.1Hkb/Nedd4l^tm1.1Hkb; Tg(SFTPC-rtTA)5Jaw/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6 * FVB/N * SJL

mortality/aging

postnatal lethality, complete penetrance ( J:169296 )

• mice die between 2 and 3 weeks of age likely from airway obstruction and asphyxiation

respiratory system

lung inflammation ( J:169296 )

• mice exhibit large dense patches consisting of infiltrating neutrophils that is not secondary to bacterial infection unlike control mice

• however, treatment with amiloride reduces inflammation

abnormal lung morphology ( J:169296 )

• mice exhibit decreased lung wet/dry ratio compared with control mice

• however, treatment with amiloride improves lung defects

pulmonary fibrosis ( J:169296 )

• mice exhibit cystic fibrosis-like defects unlike control mice

increased respiratory mucosa goblet cell number ( J:169296 )

• mice exhibit increased nonciliated mucus secreting (mostly goblet) cells in the trachea unlike control mice

abnormal trachea morphology ( J:169296 )

• mice exhibit increased nonciliated mucus secreting (mostly goblet) cells in the trachea unlike control mice

abnormal tracheal ciliated epithelium morphology ( J:169296 )

• airway periciliary liquid layer in the trachea is decreased in height compared to in control mice

immune system

lung inflammation ( J:169296 )

• mice exhibit large dense patches consisting of infiltrating neutrophils that is not secondary to bacterial infection unlike control mice

• however, treatment with amiloride reduces inflammation

Genotype
MGI:3613082

cn44

• Allelic Composition: Lama5^tm1Jhm/Lama5^tm2Jhm; Tg(SFTPC-rtTA)5Jaw/?; Tg(tetO-cre)1Jaw/?
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ

mortality/aging

neonatal lethality, complete penetrance ( J:104565 )

• animals exposed to doxycycline from E6.5 die within a few hours of birth from respiratory failure

respiratory system

abnormal lung vasculature morphology ( J:104565 )

• severely reduced density of lung capillary network in newborn animals exposed to doxycycline from E6.5, associated with reduced VEGF expression in mutant lungs

abnormal lung development ( J:104565 )

• areas of thin lung mesenchyme and upregulation of integrin alpha 3 (Lama5 receptor) in newborn animals exposed to doxycycline from E6.5

thin lung-associated mesenchyme ( J:104565 )

• areas of thin lung mesenchyme in newborn animals exposed to doxycycline from E6.5

pulmonary hypoplasia ( J:104565 )

• total lung parenchyma is reduced

abnormal pulmonary alveolus morphology ( J:104565 )

• airspaces of newborn animals exposed to doxycycline from E6.5 are filled with amorphous proteinaceous material and cellular debris not seen in controls

abnormal pulmonary alveolus epithelium morphology ( J:104565 )

• delayed or impaired differentiation of distal alveolar epithelium in newborn animals exposed to doxycycline from E6.5

• mutant peripheral airspaces are often lined with cuboidal epithelium

absent type I pneumocytes ( J:104565 )

• virtual absence of alveolar type I cells in newborn animals exposed to doxycycline from E6.5

decreased type II pneumocyte number ( J:104565 )

• significant reduction of alveolar type II cells in newborn animals exposed to doxycycline from E6.5

overexpanded pulmonary alveolus ( J:104565 )

• enlarged distal airspaces in newborn animals exposed to doxycycline from E6.5

respiratory distress ( J:104565 )

• newborn animals exposed to doxycycline from E6.5 display labored breathing

respiratory failure ( J:104565 )

homeostasis/metabolism

cyanosis ( J:104565 )

• newborn animals exposed to doxycycline from E6.5 display cyanosis

cardiovascular system

abnormal lung vasculature morphology ( J:104565 )

• severely reduced density of lung capillary network in newborn animals exposed to doxycycline from E6.5, associated with reduced VEGF expression in mutant lungs

cellular

increased apoptosis ( J:104565 )

• in lungs of newborn animals exposed to doxycycline starting at E6.5

decreased cell proliferation ( J:104565 )

• in lungs of newborn animals exposed to doxycycline from E6.5

Genotype
MGI:5694225

cn45

• Allelic Composition: Fgfr1^tm1Jpa/Fgfr1^tm1Jpa; Fgfr2^tm1Dor/Fgfr2^tm1Dor; Tg(Msx2-rtTA)888Lma/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6

reproductive system

genital tubercle hypoplasia ( J:223057 )

• underdeveloped from E11.5

• deficiency in proximodistal outgrowth at E12.5

• smaller in size at E15.5 with a lack in mesenchymal patterning

abnormal reproductive system physiology ( J:223057 )

• at E11.0, genital mesenchyme exhibits a reduction in cell proliferation compared with in wild-type mice

• however, apoptosis rates are normal

Genotype
MGI:5538307

cn46

• Allelic Composition: Ctnnb1^tm2Kem/Ctnnb1^tm2Kem; Tg(KRT5-rtTA)#Glk/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * FVB/N

integument

increased hair follicle apoptosis ( J:204142 )

• with doxycycline induction from P8, hair follicles contain numerous apoptotic cells (more than in mutants with transgenic expression of Dkk1, or Dkk1 and Kremen

abnormal hair growth ( J:204142 )

• with doxycline induction from P30, mutants completely lack external hair when examined at P100-102

abnormal hair follicle morphology ( J:204142 )

• with doxycycline induction from P8 hair follicles in mutants display structural defects at P24, including widened infundibulum and loss of a clearly distinguishable secondary hair germ

abnormal hair follicle infundibulum morphology ( J:204142 )

• with doxycycline induction from P8 hair follicles display a widened infundibulum at P24

decreased hair follicle number ( J:204142 )

• with doxycycline induction from P30, hair follicles are mainly absent in mutants

hair follicle degeneration ( J:204142 )

• with doxycycline induction from P30, hair follicles degrade and form utricles by P180

abnormal hair cycle anagen phase ( J:204142 )

• when doxycline induction is performed at P4 or P7 and dorsal skin harvested at P8 or P14, hair follicles in treated skin show cessation of anagen

• with doxycycline induction from P50 and hair plucking at P54, proliferation of secondary hair germ cells of follicles is decreased or absent and a new hair growth phase is not observed by P57

• with induction from P17 (catagen phase), follicles fail to enter anagen

accelerated hair follicle regression ( J:204142 )

• when doxycline induction is performed at P4 or P7 and dorsal skin harvested at P8 or P14, hair follicles in treated skin show entry into a premature regression phase compared to controls

abnormal dermis papillary layer morphology ( J:204142 )

• dermal papillary cells are observed 'stranded' in the epidermis or at the end of 'streamers' of degenerating hair follicles

abnormal epidermal layer morphology ( J:204142 )

• when doxycline induction is performed from P4 to P60, enlargement of intercellular spaces and some cell membrane protrusions are observed in some areas of mutant skins

thick epidermis stratum basale ( J:204142 )

• when doxycline induction is performed from P4 to P60, expansion of the basal layer is observed

thick epidermis suprabasal layer ( J:204142 )

• when doxycline induction is performed from P4 to P60, expansion of the suprabasal layer is observed

abnormal keratinocyte morphology ( J:204142 )

• when doxycline induction is performed from P4 to P60, some keratinocytes display long membranous protrusions

thick epidermis ( J:204142 )

• when doxycline induction is performed from P4 to P60, epidermis displays thickening and hyperproliferation

• with doxycycline induction from P30, epidermis is thickened at P100

cellular

increased hair follicle apoptosis ( J:204142 )

• with doxycycline induction from P8, hair follicles contain numerous apoptotic cells (more than in mutants with transgenic expression of Dkk1, or Dkk1 and Kremen

Genotype
MGI:5490536

cn47

• Allelic Composition: Adgrf5^tm1.1Bstc/Adgrf5^tm1.2Bstc; Tg(SFTPC-rtTA)5Jaw/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129S4/SvJae * C57BL/6 * C57BL/6J

homeostasis/metabolism

abnormal lipid level ( J:196943 )

• increased phosphatidylcholine in the bronchoalveolar lavage fluid of doxycycline-treated mice

increased cholesterol level ( J:196943 )

• in the bronchoalveolar lavage fluid of doxycycline-treated mice

respiratory system

increased surfactant secretion ( J:196943 )

• increased surfactant protein A, B, C and D in the whole lung lysate of doxycycline-treated mice

Genotype
MGI:6392322

cn48

• Allelic Composition: Tulp3^{tm1c(EUCOMM)Hmgu}/Tulp3^{tm1c(EUCOMM)Hmgu}; Pkd1^tm2Ggg/Pkd1⁺; Tg(Pax8-rtTA2S*M2)1Koes/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129S4/SvJae * C57BL/6 * C57BL/6N * DBA * SJL

renal/urinary system

polycystic kidney ( J:284006 )

• mice treated with doxycycline (Dox) at P0 and analyzed at P14 show development of kidney cysts, with increased kidney weight/body weight ratio and more numerous and larger cysts than single conditional Tulp3 homozygotes

• however, mice treated with Dox at P28 and analyzed at 18 weeks of age show amelioration of the cystic phenotype with no difference in cystic index

increased kidney weight ( J:284006 )

• mice treated with doxycycline (Dox) at P0 and analyzed at P14 show increased kidney weight/body weight ratio due to cysts

• mice treated with Dox at P28 for 2 weeks and analyzed at 18 weeks of age show a modest elevation of kidney weight/body weight ratio

dilated renal tubule ( J:284006 )

• mice treated with Dox at P28 for 2 weeks and analyzed at 18 weeks of age show larger tubule dilations

homeostasis/metabolism

increased blood urea nitrogen level ( J:284006 )

• mice treated with Dox at P0 show elevated blood urea nitrogen levels

• however, mice treated with Dox at P28 and analyzed at 18 weeks of age show no differences in blood urea nitrogen levels

growth/size/body

polycystic kidney ( J:284006 )

• mice treated with doxycycline (Dox) at P0 and analyzed at P14 show development of kidney cysts, with increased kidney weight/body weight ratio and more numerous and larger cysts than single conditional Tulp3 homozygotes

• however, mice treated with Dox at P28 and analyzed at 18 weeks of age show amelioration of the cystic phenotype with no difference in cystic index

increased kidney weight ( J:284006 )

• mice treated with doxycycline (Dox) at P0 and analyzed at P14 show increased kidney weight/body weight ratio due to cysts

• mice treated with Dox at P28 for 2 weeks and analyzed at 18 weeks of age show a modest elevation of kidney weight/body weight ratio

Genotype
MGI:6392333

cn49

• Allelic Composition: Tulp3^{tm1c(EUCOMM)Hmgu}/Tulp3^{tm1c(EUCOMM)Hmgu}; Pkd1^tm2Ggg/Pkd1^tm2Ggg; Tg(Pax8-rtTA2S*M2)1Koes/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129S4/SvJae * C57BL/6 * C57BL/6N * DBA * SJL

renal/urinary system

polycystic kidney ( J:284006 )

• mice treated with doxycycline (Dox) at P0 and analyzed at P14 exhibit a severe cystic phenotype

• however, mice treated with Dox at P28 and analyzed at 18 weeks of age show amelioration of the cystic phenotype with no difference in cystic index

increased kidney weight ( J:284006 )

• mice treated with doxycycline (Dox) at P0 and analyzed at P14 exhibit increased kidney weight/body weight ratio due to cysts

• however, mice treated with Dox at P28 for 2 weeks and analyzed at 18 weeks of age show no differences in kidney weight/body weight ratio

homeostasis/metabolism

increased blood urea nitrogen level ( J:284006 )

• mice treated with Dox at P0 show increased blood urea nitrogen levels at P14

• however, mice treated with Dox at P28 and analyzed at 18 weeks of age show no differences in blood urea nitrogen levels

growth/size/body

polycystic kidney ( J:284006 )

• mice treated with doxycycline (Dox) at P0 and analyzed at P14 exhibit a severe cystic phenotype

• however, mice treated with Dox at P28 and analyzed at 18 weeks of age show amelioration of the cystic phenotype with no difference in cystic index

increased kidney weight ( J:284006 )

• mice treated with doxycycline (Dox) at P0 and analyzed at P14 exhibit increased kidney weight/body weight ratio due to cysts

• however, mice treated with Dox at P28 for 2 weeks and analyzed at 18 weeks of age show no differences in kidney weight/body weight ratio

Genotype
MGI:6392330

cn50

• Allelic Composition: Tulp3^{tm1c(EUCOMM)Hmgu}/Tulp3⁺; Pkd1^tm2Ggg/Pkd1^tm2Ggg; Tg(Pax8-rtTA2S*M2)1Koes/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129S4/SvJae * C57BL/6 * C57BL/6N * DBA * SJL

renal/urinary system

polycystic kidney ( J:284006 )

• mice treated with doxycycline (Dox) at P0 and analyzed at P14 exhibit a severe cystic phenotype

• mice treated with Dox a P28 for 2 weeks and analyzed at 18 weeks show an intermediate cystic phenotype, with cystic index lower than conditional Pkd1 homozygotes but higher than in double Tulp3 and Pkd1 homozygotes

increased kidney weight ( J:284006 )

• mice treated with doxycycline (Dox) at P0 and analyzed at P14 exhibit increased kidney weight/body weight ratio due to cysts

• mice treated with Dox a P28 for 2 weeks and analyzed at 18 weeks show an intermediate kidney weight/body weight ratio, with lower ratio than conditional Pkd1 homozygotes but higher ratio than in double Tulp3 and Pkd1 homozygotes

homeostasis/metabolism

increased blood urea nitrogen level ( J:284006 )

• mice treated with Dox at P0 show increased blood urea nitrogen levels at P14

• mice treated with Dox a P28 for 2 weeks and analyzed at 18 weeks show an intermediate level of blood urea nitrogen, with lower level than conditional Pkd1 homozygotes but higher level than in double Tulp3 and Pkd1 homozygotes

growth/size/body

polycystic kidney ( J:284006 )

• mice treated with doxycycline (Dox) at P0 and analyzed at P14 exhibit a severe cystic phenotype

• mice treated with Dox a P28 for 2 weeks and analyzed at 18 weeks show an intermediate cystic phenotype, with cystic index lower than conditional Pkd1 homozygotes but higher than in double Tulp3 and Pkd1 homozygotes

increased kidney weight ( J:284006 )

• mice treated with doxycycline (Dox) at P0 and analyzed at P14 exhibit increased kidney weight/body weight ratio due to cysts

• mice treated with Dox a P28 for 2 weeks and analyzed at 18 weeks show an intermediate kidney weight/body weight ratio, with lower ratio than conditional Pkd1 homozygotes but higher ratio than in double Tulp3 and Pkd1 homozygotes

Genotype
MGI:6392328

cn51

• Allelic Composition: Pkd1^tm2Ggg/Pkd1^tm2Ggg; Tg(Pax8-rtTA2S*M2)1Koes/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129S4/SvJae * C57BL/6 * C57BL/6N * DBA * SJL

renal/urinary system

polycystic kidney ( J:284006 )

• mice treated with Dox at P0 and analyzed at P14 exhibit a severe cystic phenotype

• mice treated with Dox at P28 for 2 weeks and analyzed at 18 weeks develop severe cystic kidneys

increased kidney weight ( J:284006 )

• mice treated with doxycycline (Dox) at P0 and analyzed at P14 exhibit increased kidney weight/body weight ratio due to cysts

• mice treated with Dox at P28 for 2 weeks and analyzed at 18 weeks exhibit increased kidney weight/body weight ratio due to cysts

homeostasis/metabolism

increased blood urea nitrogen level ( J:284006 )

• mice treated with Dox at P0 show increased blood urea nitrogen levels at P14

• mice treated with Dox at P28 for 2 weeks show increased blood urea nitrogen levels at 18 weeks of age

growth/size/body

polycystic kidney ( J:284006 )

• mice treated with Dox at P0 and analyzed at P14 exhibit a severe cystic phenotype

• mice treated with Dox at P28 for 2 weeks and analyzed at 18 weeks develop severe cystic kidneys

increased kidney weight ( J:284006 )

• mice treated with doxycycline (Dox) at P0 and analyzed at P14 exhibit increased kidney weight/body weight ratio due to cysts

• mice treated with Dox at P28 for 2 weeks and analyzed at 18 weeks exhibit increased kidney weight/body weight ratio due to cysts

Genotype
MGI:6392326

cn52

• Allelic Composition: Pkd1^tm2Ggg/Pkd1⁺; Tg(Pax8-rtTA2S*M2)1Koes/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129S4/SvJae * C57BL/6 * C57BL/6N * DBA * SJL

renal/urinary system

renal/urinary system phenotype ( J:284006 )

N • mice treated with doxycycline (Dox) at P0 and analyzed at P14 do not form kidney cysts

Genotype
MGI:5538309

cn53

• Allelic Composition: Tg(KRT5-rtTA)#Glk/0; Tg(tetO-cre)1Jaw/0; Wls^tm1.1Lan/Wls^tm1.1Lan
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6 * FVB/N

integument

abnormal hair follicle morphology ( J:204142 )

• in P60 animals, hair follicle structures are retained in absence of external hair, but display abnormalities including cyst formation

abnormal hair cycle catagen phase ( J:204142 )

• cre induction at P4 causes hair follicle regression by P14 without loss of bulge stem cell markers

abnormal epidermal layer morphology ( J:204142 )

• when doxycline induction is performed from P4 to P18, epidermis exhibits increased proliferation as well as expanded expression of basal and suprabasal markers and hyperproliferation markers

• when doxycline induction is performed from P4 to P18, enlargement of intercellular spaces and some cell membrane protrusions are observed in some areas of mutant skins at P60

• defects of the interfollicular epidermis similar to those observed in conditional Ctnnb1 mutants are seen in induced mutants

abnormal keratinocyte morphology ( J:204142 )

immune system

cutaneous mastocytosis ( J:204142 )

• with doxycycline induction from P4-P18, mast cell number in the dermis is increased at P60

hematopoietic system

cutaneous mastocytosis ( J:204142 )

• with doxycycline induction from P4-P18, mast cell number in the dermis is increased at P60

Genotype
MGI:5431583

cn54

• Allelic Composition: Dicer1^tm1Smr/Dicer1^tm1Smr; Tg(KRT5-rtTA)1Glk/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129S7/SvEvBrd * C57BL/6 * FVB/N

integument

integument phenotype ( J:183487 )

N • doxycycline-treated mice retain hair follicle stem cells in early telogen and anagen

abnormal coat/ hair morphology ( J:183487 )

• hair phenotype in doxycycline-treated mice appears more rapidly than in Drosha^tm1Litt/Drosha^tm1Litt Tg(KRT5-rtTA)1Glk Tg(tetO-cre)1Jaw mice

abnormal hair growth ( J:183487 )

• failure of hair regrowth in doxycycline-treated mice

• failure of regression at P20 in doxycycline-treated mice and remained in an abnormal growth phase

• following hair plucking, doxycycline-treated mice fail to sustain hair growth unlike control mice

alopecia ( J:183487 )

• after P14 in doxycycline-treated mice

waved hair ( J:183487 )

• external hair becomes wavy between P12 and P14 in doxycycline-treated mice

abnormal hair shaft morphology ( J:183487 )

• in doxycycline-treated mice likely due to matrix cell apoptosis

abnormal hair follicle morphology ( J:183487 )

• at P17 in doxycycline-treated mice after degradation begins

abnormal hair follicle inner root sheath morphology ( J:183487 )

• fewer differentiation cell in doxycycline-treated mice following plucking-induced anagen initiation

abnormal hair follicle bulge morphology ( J:183487 )

• at P59 doxycycline-treated mice exhibit loss of bulge stem cells unlike in control mice

• however, bulge stem cells are present at P20 and P22

hair follicle degeneration ( J:183487 )

• with extrusion of abnormally keratinized cellular material in doxycycline-treated mice

small hair follicles ( J:183487 )

• in doxycycline-treated mice following plucking-induced anagen initiation

abnormal hair cycle catagen phase ( J:183487 )

• failure of catagen in doxycycline-treated mice

abnormal hair follicle regression ( J:183487 )

• failure of regression at P20 in doxycycline-treated mice

epidermal hyperplasia ( J:183487 )

• by P20, doxycycline-treated mice exhibit thickened interfollicular epidermis compared with control mice

dry skin ( J:183487 )

• mice treated with doxycycline exhibit a temporary phenotype of dry scaly skin that is resolved in an anterior-posterior direction

scaly skin ( J:183487 )

• mice treated with doxycycline exhibit a temporary phenotype of dry scaly skin that is resolved in an anterior-posterior direction

abnormal skin physiology ( J:183487 )

cellular

increased apoptosis ( J:183487 )

• doxycycline-treated mice exhibit matrix cell apoptosis with DNA damage response unlike in control mice

growth/size/body

decreased body size ( J:183487 )

• in doxycycline-treated mice

Genotype
MGI:3716394

cn55

• Allelic Composition: Kras^tm4Tyj/Kras⁺; Tg(SFTPC-rtTA)5Jaw/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129/Sv * C57BL/6

mortality/aging

postnatal lethality, complete penetrance ( J:119477 )

• death in the early postnatal period

respiratory system

abnormal branching involved in lung morphogenesis ( J:119477 )

• with doxycycline treatment beginning at E6.5, a dramatic lung branching defect is observed

• at E16.5, lungs show even more severe defects than in Kras:Meox2-cre embryos, with large epithelial-lined pouches in place of finely branched network of airways seen in wild-type

• branching defect persists through late gestation leading to early postnatal lethality

abnormal lung epithelium morphology ( J:119477 )

• branching defect originates in epithelium rather than mesenchyme

abnormal bronchus epithelium morphology ( J:119477 )

• markers of ciliated and Clara cells in the bronchi are significantly reduced at E18.5 compared to controls, indicating block in differentiation of lung epithelium

Genotype
MGI:3051987

cn56

• Allelic Composition: Bdnf^tm3Jae/Bdnf^tm3Jae; Tg(Eno2tTA)5030Nes/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129/Sv * C57BL/6 * ICR * SJL

behavior/neurological

impaired behavioral response to xenobiotic ( J:91563 )

• no response is seen to the antidepressant desipramine in mutants when doxycycline treatment is stopped at 3 months of age

abnormal contextual conditioning behavior ( J:91563 )

• contextual learning is impaired in mutants when doxycycline treatment is stopped at 3 months of age compared to mutant littermates maintained on doxycycline

• contextual learning is virtually absent in mutants when no doxycycline treatment is given throughout development

abnormal cued conditioning behavior ( J:91563 )

• cued learning is normal in mutants when doxycycline treatment is stopped at 3 months of age but impaired when no doxycycline treatment is given throughout development

hyperactivity ( J:91563 )

• mutants bred without doxycycline treatment are hyperactive compared to mutants bred with doxycycline treatment

• hyperactivity is not seen when doxycycline treatment is stopped at 3 months of a

nervous system

reduced long-term potentiation ( J:91563 )

• long term potentiation is impaired requiring a greater amplitude stimulus to evoke any response in mutants when doxycycline treatment is stopped at 3 months of age compared to mutant littermates maintained on doxycycline

Genotype
MGI:5567830

cn57

• Allelic Composition: Gt(ROSA)26Sor^tm1(EYFP)Cos/Gt(ROSA)26Sor⁺; Hprt1^{tm1(Ins2-HBEGF)Herr}/Y; Tg(Gcg-rtTA)#Herr/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: 129X1/SvJ * C57BL/6

endocrine/exocrine glands

abnormal pancreatic alpha cell differentiation ( J:159291 )

♂ • alpha cells in diphtheria-treated mice transdifferentiate into beta cells

cellular

abnormal pancreatic alpha cell differentiation ( J:159291 )

♂ • alpha cells in diphtheria-treated mice transdifferentiate into beta cells

Genotype
MGI:5571470

cn58

• Allelic Composition: Adam17^tm1.1Wesh/Adam17^tm1.1Wesh; Tg(Scgb1a1-rtTA)2Jaw/0; Tg(tetO-cre)1Jaw/0; Twist2^{tm1.1(cre)Dor}/Twist2⁺
• Genetic Background: involves: 129X1/SvJ * C57BL/6 * FVB/N

mortality/aging

mortality/aging ( J:210193 )

N • doxycycline-treated mice exhibit normal neonatal survival

respiratory system

abnormal lung vasculature morphology ( J:210193 )

• reduced pulmonary capillary formation in doxycycline-treated mice

abnormal lung saccule morphology ( J:210193 )

• doxycycline-treated mice exhibit enlarged airspaces with fewer number of saccules and reduced epithelial cell differentiation compared with control mice

cellular

decreased cell proliferation ( J:210193 )

• in the lungs of doxycycline-treated mice

cardiovascular system

abnormal lung vasculature morphology ( J:210193 )

• reduced pulmonary capillary formation in doxycycline-treated mice

Genotype
MGI:5905988

cn59

• Allelic Composition: Tg(KRT5-rtTA)#Glk/0; Tg(tetO-cre)1Jaw/0; Wnt10a^tm1Smr/Wnt10a^tm1Smr
• Genetic Background: involves: 129X1/SvJ * C57BL/6 * FVB/N

integument

enlarged sebaceous gland ( J:242196 )

• when treated with doxycycline at P25

abnormal sweat gland morphology ( J:242196 )

• fail to extend when treated with doxycycline in early postnatal life

• regression of sweat glands when treated with doxycycline at P20

abnormal sebaceous lipid secretion ( J:242196 )

• elevated lipid production when treated with doxycycline at P25

hypohidrosis ( J:242196 )

• when treated with doxycycline at P20

small hair follicles ( J:242196 )

• minitaturized when treated with doxycycline at P25

abnormal hair cycle anagen phase ( J:242196 )

• delayed initiation of anagen until P29, when treated with doxycycline at P18

accelerated hair follicle regression ( J:242196 )

• premature when treated with doxycycline at P9

• however, hair follicle regression isnt observed when treated with doxycycline at P25

abnormal hair follicle physiology ( J:242196 )

• slightly reduced proliferation when treated with doxycycline at P25

craniofacial

abnormal tongue morphology ( J:242196 )

• flattened surface when treated with doxycycline in early postnatal life

abnormal filiform papillae morphology ( J:242196 )

• progressive from P7 when treated with doxycycline in early postnatal life

abnormal fungiform papillae morphology ( J:242196 )

• progressive from P7 when treated with doxycycline in early postnatal life

abnormal gustatory papilla taste bud morphology ( J:242196 )

• miniaturized when treated with doxycycline in early postnatal life

• decreased taste bud in fungiform and circumvallate papillae when treated with doxycycline in early postnatal life

cellular

decreased cell proliferation ( J:242196 )

• decreased basal cell proliferation in the filiform papillae and plantar epithelium, fungiform and circumvallate taste buds and sweat buds when treated with doxycycline at in either the early postnatal period, or in adult life

taste/olfaction

abnormal gustatory papilla taste bud morphology ( J:242196 )

• miniaturized when treated with doxycycline in early postnatal life

• decreased taste bud in fungiform and circumvallate papillae when treated with doxycycline in early postnatal life

digestive/alimentary system

abnormal tongue morphology ( J:242196 )

• flattened surface when treated with doxycycline in early postnatal life

abnormal filiform papillae morphology ( J:242196 )

• progressive from P7 when treated with doxycycline in early postnatal life

abnormal fungiform papillae morphology ( J:242196 )

• progressive from P7 when treated with doxycycline in early postnatal life

abnormal gustatory papilla taste bud morphology ( J:242196 )

• miniaturized when treated with doxycycline in early postnatal life

• decreased taste bud in fungiform and circumvallate papillae when treated with doxycycline in early postnatal life

endocrine/exocrine glands

enlarged sebaceous gland ( J:242196 )

• when treated with doxycycline at P25

abnormal sweat gland morphology ( J:242196 )

• fail to extend when treated with doxycycline in early postnatal life

• regression of sweat glands when treated with doxycycline at P20

abnormal sebaceous lipid secretion ( J:242196 )

• elevated lipid production when treated with doxycycline at P25

hypohidrosis ( J:242196 )

• when treated with doxycycline at P20

growth/size/body

abnormal tongue morphology ( J:242196 )

• flattened surface when treated with doxycycline in early postnatal life

abnormal filiform papillae morphology ( J:242196 )

• progressive from P7 when treated with doxycycline in early postnatal life

abnormal fungiform papillae morphology ( J:242196 )

• progressive from P7 when treated with doxycycline in early postnatal life

abnormal gustatory papilla taste bud morphology ( J:242196 )

• miniaturized when treated with doxycycline in early postnatal life

• decreased taste bud in fungiform and circumvallate papillae when treated with doxycycline in early postnatal life

Genotype
MGI:4940890

cn60

• Allelic Composition: Pcyt1a^tm1Irt/Pcyt1a^tm1Irt; Tg(SFTPC-rtTA)5Jaw/0; Tg(tetO-cre)1Jaw/Tg(tetO-cre)1Jaw
• Genetic Background: involves: C57BL/6J * FVB/N

mortality/aging

neonatal lethality, complete penetrance ( J:118292 )

• all newborn mice exposed to doxycycline from E6.5 to E7.5 die within 10 min of delivery

• all mice exposed to doxycycline at either E10.5 or E12.5 and continuing until birth (E18.5 to E19.5) exhibit neonatal lethality

neonatal lethality, incomplete penetrance ( J:118292 )

• only 10% of mice exposed to doxycycline from E16.5 to term exhibit neonatal death

• neonatal viability is also significantly reduced when doxycycline is administered between E8.5 and E12.5

respiratory system

abnormal lung vasculature morphology ( J:118292 )

• capillary leakage and macrophage accumulation within the alveolar space of doxycycline-exposed newborn mice

pulmonary vascular congestion ( J:118292 )

• pulmonary congestions in perinatal lung sections from doxycycline-exposed mice

abnormal lung saccule morphology ( J:118292 )

• at E19.5 (birth), dilation of peripheral lung saccules is reduced and the septa remain thickened in doxycycline-exposed mice

abnormal type II pneumocyte morphology ( J:118292 )

• in doxycycline-exposed mice, type II alveolar cells display Golgi complex abnormalities, aberrant lamellar body formation, fewer and shorter apical microvilli, and freqeunt accumulation of lipid droplets consistent with increased pulmonary triglyceride levels

• in contrast, the ultrastructure of type I alveolar cells remains normal

decreased alveolar lamellar body number ( J:118292 )

• fewer secretary vesicles or mature lamellar bodies in doxycycline-exposed mice

decreased type II pneumocyte number ( J:118292 )

• at E19.5 (birth), the number of type II alveolar cells is markedly reduced in the terminal lung saccules of all doxycycline-exposed mice

abnormal pulmonary alveolar sac morphology ( J:118292 )

• nondilated alveolar saccules in doxycycline-exposed newborn mice

increased pulmonary alveolus wall thickness ( J:118292 )

• in doxycycline-exposed mice, alveolar walls are thickened but still lined with organized type I and type II cells

atelectasis ( J:118292 )

• focal or extensive atelectasis seen in perinatal lung sections from mice exposed to doxycycline from E6.5 to E7.5

• all neonatal lungs from mice exposed to doxycycline from E6.5 to E7.5 fail to inflate and sink in saline, unlike wild-type neonatal lungs

• however, lungs of viable mice exposed to doxycycline from E16.5 to term appear inflated and show normal lung morphology

pulmonary hyaline membrane formation ( J:118292 )

• hyaline membrane formation seen in perinatal lung sections from mice exposed to doxycycline from E6.5 to E7.5

respiratory distress ( J:118292 )

• all mice exposed to doxycycline from E6.5 to E7.5 develop severe respiratory distress immediately after birth

• also seen in all mice exposed to doxycycline at either E10.5 or E12.5 and continuing until birth (E18.5 to E19.5)

abnormal surfactant composition ( J:118292 )

• the phosphatidylcholine (PtdCho) content is significantly reduced when doxycycline is administered between E8.5 and E12.5 or between E12.5 and E16.5, but not prior to E9.5

• at E17.5, the PtdCho content is significantly reduced in mice exposed to doxycycline from E0 to E17, with a severe decrease in the proportion of dipalmitoyl-PtdCho, suggesting a selective depletion of the C16:0 fatty acid; however, neither phosphatidylethanolamine nor cholesterol is significantly reduced

• total BAL fluid contains significantly less phospholipid per lung; both the large (LA) and small (SA) aggregate fractions are severely depleted in total phospholipid

• the reduction in surfactant protein is less than that in total phospholipid resulting in a 4.7-, 2.8-, and 7.4-fold increase in the protein:phospholipid ratio in BAL, LA, and SA, respectively

abnormal surfactant secretion ( J:118292 )

• in mice exposed to doxycycline from E0 to E17, phosphatidylcholine (PtdCho) formation is blocked and surfactant fatty acid synthesis is shunted into the triglyceride pool

• surfactant protein SP-A, SP-C, and SP-D levels are significantly reduced, whereas SP-B protein content is elevated

homeostasis/metabolism

cyanosis ( J:118292 )

• all newborn mice exposed to doxycycline from E6.5 to E7.5 become cyanotic

increased triglyceride level ( J:118292 )

• significantly increased triglyceride levels in neonatal lungs from mice exposed to doxycyclin from E0 to E17, with a similar increase in the proportion of species containing palmitic acid (C16:0), esp. in the species containing 48 and 60 carbons

cardiovascular system

abnormal lung vasculature morphology ( J:118292 )

• capillary leakage and macrophage accumulation within the alveolar space of doxycycline-exposed newborn mice

pulmonary vascular congestion ( J:118292 )

• pulmonary congestions in perinatal lung sections from doxycycline-exposed mice

Genotype
MGI:3713390

cn61

• Allelic Composition: Foxa2^{tm1.1(rtTa)Moon}/Foxa2^{tm1.1(rtTa)Moon}; Gt(ROSA)26Sor^tm1Sor/?; Tg(tetO-cre)1Jaw/?
• Genetic Background: involves: C57BL/6 * SJL

normal phenotype

no abnormal phenotype detected ( J:119721 )

• mice are normal

Genotype
MGI:3051584

cn62

• Allelic Composition: Shh^tm1Amc/Shh^tm2Amc; Tg(SFTPC-rtTA)5Jaw/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: FVB/N

mortality/aging

neonatal lethality, complete penetrance ( J:91723 )

• mutants die shortly after birth when doxycycline is administered throughout gestation

• in the absence of doxycycline treatment mutants are viable

respiratory system

abnormal lung morphology ( J:91723 )

• lung and airway malformations are seen when doxycycline exposure occurs between E0.5 and E13.5

• doxycycline exposure after E13.5 does not result in any pulmonary or extrapulmonary abnormalities

lung cyst ( J:91723 )

• cysts are seen in the peripheral lung tissue

abnormal branching involved in lung morphogenesis ( J:91723 )

• branching morphogenesis is abnormal with doxycycline treatment

pulmonary hypoplasia ( J:91723 )

• lungs are hypoplastic after doxycycline exposure

abnormal bronchus morphology ( J:91723 )

• peripheral tubule dilation is seen with doxycycline exposure

abnormal trachea morphology ( J:91723 )

• tracheal abnormalities are seen

• doxycycline exposure before E8.5 or after E13.5 does not result in tracheal abnormalities

abnormal tracheal cartilage morphology ( J:91723 )

• the cartilaginous rings that normal surround the trachea are malformed with incomplete rings found along the ventral midline after doxycycline exposure

decreased tracheal cartilage ring number ( J:91723 )

• fewer cartilaginous rings are seen with doxycycline treatment

skeleton

abnormal tracheal cartilage morphology ( J:91723 )

• the cartilaginous rings that normal surround the trachea are malformed with incomplete rings found along the ventral midline after doxycycline exposure

decreased tracheal cartilage ring number ( J:91723 )

• fewer cartilaginous rings are seen with doxycycline treatment

growth/size/body

lung cyst ( J:91723 )

• cysts are seen in the peripheral lung tissue

Genotype
MGI:3051583

cn63

• Allelic Composition: Shh^tm2Amc/Shh^tm2Amc; Tg(SFTPC-rtTA)5Jaw/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: involves: FVB/N

mortality/aging

neonatal lethality, complete penetrance ( J:91723 )

• mutants die shortly after birth when doxycycline is administered throughout gestation

• in the absence of doxycycline mutants are viable

respiratory system

abnormal lung morphology ( J:91723 )

• lung and airway malformations are seen when doxycycline exposure occurs between E0.5 and E13.5

• doxycycline exposure after E13.5 does not result in any pulmonary or extrapulmonary abnormalities

lung cyst ( J:91723 )

• cysts that contain neuroepithelial cells are seen in the peripheral lung tissue

abnormal branching involved in lung morphogenesis ( J:91723 )

• branching morphogenesis is abnormal

pulmonary hypoplasia ( J:91723 )

• lungs are hypoplastic when doxycycline is administered throughout gestation

abnormal bronchus morphology ( J:91723 )

• peripheral tubule dilation is seen after doxycycline exposure

abnormal trachea morphology ( J:91723 )

• tracheal abnormalities are seen

• doxycycline exposure before E8.5 or after E13.5 does not result in tracheal abnormalities

abnormal tracheal cartilage morphology ( J:91723 )

• the cartilaginous rings that normal surround the trachea are malformed with incomplete rings found along the ventral midline after doxycycline exposure

decreased tracheal cartilage ring number ( J:91723 )

• fewer cartilaginous rings are seen after doxycycline exposure

skeleton

abnormal tracheal cartilage morphology ( J:91723 )

• the cartilaginous rings that normal surround the trachea are malformed with incomplete rings found along the ventral midline after doxycycline exposure

decreased tracheal cartilage ring number ( J:91723 )

• fewer cartilaginous rings are seen after doxycycline exposure

growth/size/body

lung cyst ( J:91723 )

• cysts that contain neuroepithelial cells are seen in the peripheral lung tissue

Genotype
MGI:3036450

cn64

• Allelic Composition: Foxa2^tm1Khk/Foxa2^tm1Khk; Tg(Scgb1a1-rtTA)1Jaw/0; Tg(tetO-cre)1Jaw/0
• Genetic Background: Not Specified

immune system

immune system phenotype ( J:88601 )

N • no increase in the number of neutrophils or macrophages in mice treated with doxycycline from E0 through P16

respiratory system

increased respiratory mucosa goblet cell number ( J:88601 )

• goblet cell hyperplasia, associated with the accumulation of both neutral and acidic mucins, in the larger airways of mice treated with doxycycline from E0 through P16

• neither airspace nor alveolar morphological abnormalities were detected

abnormal respiratory mechanics ( J:88601 )

increased airway resistance ( J:88601 )

• increased in mice treated with doxycycline

decreased lung compliance ( J:88601 )

• decreased in mice treated with doxycycline