Phenotypes associated with this allele

• Allele Symbol: Tg(SFTPC-rtTA)5Jaw
• Allele Name: transgene insertion 5, Jeffrey A Whitsett
• Allele ID: MGI:2445716
• Summary: 35 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
cn1	Foxa2^tm1Khk/Foxa2^tm1Khk Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * 129P2/OlaHsd * C57BL/6	MGI:3036449
cn2	Sox9^tm1Gsr/Sox9^tm1Gsr Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * 129P2/OlaHsd * C57BL/6	MGI:4888973
cn3	Stat3^tm2Aki/Stat3^tm2Aki Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * 129P2/OlaHsd * C57BL/6	MGI:4888972
cn4	Met^tm1Sst/Met^tm1Sst Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * 129P2/OlaHsd * C57BL/6	MGI:4938180
cn5	Pten^tm2Mak/Pten^tm2Mak Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * 129P2/OlaHsd * C57BL/6 * C57BL/6J	MGI:4950587
cn6	Hif1a^tm3Rsjo/Hif1a^tm3Rsjo Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:4418552
cn7	Pten^tm1Hwu/Pten^tm1Hwu Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * 129S4/SvJae * C57BL/6 * FVB/N	MGI:4882116
cn8	Cebpa^tm1Dgt/Cebpa^tm1Dgt Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * 129S6/SvEvTac * C57BL/6	MGI:4942158
cn9	Foxm1^tm1Rhc/Foxm1^tm1Rhc Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * 129X1/SvJ * C57BL/6	MGI:4889055
cn10	Cebpa^tm1Gonz/Cebpa^tm1Gonz Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * 129X1/SvJ * C57BL/6 * FVB/N	MGI:3809493
cn11	Itga3^tm1Hap/Itga3^tm1Hap Tg(CAG-Bgeo/GFP)21Lbe/? Tg(SFTPC-rtTA)5Jaw/? Tg(tetO-cre)1Jaw/?	involves: 129 * C57BL/6	MGI:3833134
cn12	Eif4b^tm1.1Smoc/Eif4b^+ Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * C57BL/6	MGI:6790454
cn13	Eif4b^tm1.1Smoc/Eif4b^tm1.1Smoc Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * C57BL/6	MGI:6790452
cn14	Tg(CAG-cat,-Il18)#Thos/0 Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * C57BL/6	MGI:5688535
cn15	Klf5^tm1Jaw/Klf5^tm1Jaw Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * C57BL/6	MGI:3806650
cn16	Itga3^tm1Hap/Itga3^tm1Hap Tg(SFTPC-rtTA)5Jaw/? Tg(tetO-cre)1Jaw/?	involves: 129 * C57BL/6	MGI:3833133
cn17	Vegfa^tm2Gne/Vegfa^tm2Gne Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * C57BL/6	MGI:4938179
cn18	Vegfa^tm2Gne/Vegfa^+ Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129 * C57BL/6	MGI:4938194
cn19	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
cn20	Lama5^tm1Jhm/Lama5^tm2Jhm Tg(SFTPC-rtTA)5Jaw/? Tg(tetO-cre)1Jaw/?	involves: 129S1/Sv * 129X1/SvJ	MGI:3613082
cn21	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
cn22	Kras^tm4Tyj/Kras^+ Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: 129/Sv * C57BL/6	MGI:3716394
cn23	Pcyt1a^tm1Irt/Pcyt1a^tm1Irt Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/Tg(tetO-cre)1Jaw	involves: C57BL/6J * FVB/N	MGI:4940890
cn24	Shh^tm1Amc/Shh^tm2Amc Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: FVB/N	MGI:3051584
cn25	Shh^tm2Amc/Shh^tm2Amc Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0	involves: FVB/N	MGI:3051583
cx26	Fgfr3^tm1Dor/Fgfr3^tm1Dor Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-Fgf9,-EGFP)#Dor/0	involves: 129S6/SvEvTac * C57BL/6J * FVB	MGI:5538522
cx27	Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-IGF1R)1Ramo/0	involves: FVB	MGI:7265160
cx28	Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-Fgf9,-EGFP)#Dor/0	involves: FVB	MGI:5538520
cx29	Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO/CMV-KRAS*G12C)9.1Msmi/0	involves: FVB/N	MGI:3693291
cx30	Tg(tetO-Vegfa)90Ala/? Tg(SFTPC-rtTA)5Jaw/?	involves: FVB/N	MGI:3586365
cx31	Shh^tm1Amc/Shh^tm1Amc Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-Shh)1Jaw/0	involves: FVB/N	MGI:3051585
cx32	Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-PLAGL2)P3Ysy/0	involves: FVB/N	MGI:4360917
cx33	Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-Fgf9,-EGFP)#Dor/0	Not Specified	MGI:5538517
cx34	Gt(ROSA)26Sor^tm1(tetO-Sox9)Msan/Gt(ROSA)26Sor^+ Tg(SFTPC-rtTA)5Jaw/0	Not Specified	MGI:5557986
cx35	Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-MYC)36Bop/0	Not Specified	MGI:4946284

Genotype
MGI:3036449

cn1

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

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

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: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:4888972

cn3

• 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

cn4

• 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

cn5

• 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

cn6

• 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:4882116

cn7

• 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:4942158

cn8

• 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:4889055

cn9

• 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:3809493

cn10

• 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:3833134

cn11

• 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:6790454

cn12

• 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:6790452

cn13

• 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:5688535

cn14

• 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:3806650

cn15

• 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

cn16

• 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:4938179

cn17

• 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

cn18

• 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:4941006

cn19

• 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

cn20

• 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:5490536

cn21

• 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:3716394

cn22

• 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:4940890

cn23

• 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:3051584

cn24

• 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

cn25

• 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:5538522

cx26

• Allelic Composition: Fgfr3^tm1Dor/Fgfr3^tm1Dor; Tg(SFTPC-rtTA)5Jaw/0; Tg(tetO-Fgf9,-EGFP)#Dor/0
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6J * FVB

neoplasm

decreased organ/body region tumor incidence ( J:204282 )

• at 1 week or 1 month of induction with doxycycline, mutants do not exhibit formation of lung tumors and lung histology remains normal

Genotype
MGI:7265160

cx27

• Allelic Composition: Tg(SFTPC-rtTA)5Jaw/0; Tg(tetO-IGF1R)1Ramo/0
• Genetic Background: involves: FVB

neoplasm

increased lung tumor incidence ( J:271820 )

• mice administered doxycyline beginning at 21 days of age develop tumors on the lung surface as early as 90 days after doxycycline treatment

• most mice treated with doxycycline for up to 9 months exhibit visible lung tumors (2-30 tumors); tumors show multifocal adenomatous alveolar hyperplasia with papillary and solid adenomas

• mice in which doxycycline is removed after an 8-month treatment period show incomplete tumor regression

• however, bronchiolar hyperplasia is not seen in doxycycline treated mice

increased lung adenoma incidence ( J:271820 )

• solid adenomas are seen in doxycycline-treated mice

respiratory system

increased lung tumor incidence ( J:271820 )

• mice administered doxycyline beginning at 21 days of age develop tumors on the lung surface as early as 90 days after doxycycline treatment

• most mice treated with doxycycline for up to 9 months exhibit visible lung tumors (2-30 tumors); tumors show multifocal adenomatous alveolar hyperplasia with papillary and solid adenomas

• mice in which doxycycline is removed after an 8-month treatment period show incomplete tumor regression

• however, bronchiolar hyperplasia is not seen in doxycycline treated mice

increased lung adenoma incidence ( J:271820 )

• solid adenomas are seen in doxycycline-treated mice

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
lung cancer		DOID:1324	OMIM:211980 OMIM:608935 OMIM:612571 OMIM:612593 OMIM:614210	J:271820

Genotype
MGI:5538520

cx28

• Allelic Composition: Tg(SFTPC-rtTA)5Jaw/0; Tg(tetO-Fgf9,-EGFP)#Dor/0
• Genetic Background: involves: FVB

neoplasm

increased malignant tumor incidence ( J:204282 )

• 2 of 5 mutants that develop ascites after 4 months of doxycycline induction contain cells with malignant cytology

increased blastoma incidence ( J:224791 )

• doxycycline induction from E16.5 to E18.5 results in lung mesenchymal hyperplasia beneath a benign-appearing Nkx2.1 positive epithelium with histological features of Type I or cystic pleuropulmonary blastoma

increased lung tumor incidence ( J:204282 )

• one day following doxycycline administration, adult mutants exhibit formation of small nodules (epithelial clusters) on the lung surface

• papillary adenoma and papillary adenocarcinoma develop in mice treated with doxycycline for 4 and 8 days, respectively

• small tumor nodules and large tumor nodules persist in the lungs of mutants treated with doxycycline for 2-4 days followed by 1 month of doxycycline and in mutants treated with doxycycline for 2 weeks followed by 9 and 18 weeks of withdrawal, respectively

increased lung adenoma incidence ( J:204282 )

• after 4 days of doxycycline induction, nodules are histologically consistent with papillary adenoma

increased lung adenocarcinoma incidence ( J:204282 )

• after 8 days of doxycycline induction, the cells forming papillary structures become atypical with larger and hyperchromatic nuclei, consistent with papillary adenocarcinoma

cellular

increased mesenchymal cell proliferation involved in lung development ( J:224791 )

• lungs show increased mesenchymal proliferation after doxycycline induction from E10.5 to E12.5

mortality/aging

premature death ( J:204282 )

• doxycycline treated adults show a median survival of 89 days and die due to respiratory failure

respiratory system

increased mesenchymal cell proliferation involved in lung development ( J:224791 )

• lungs show increased mesenchymal proliferation after doxycycline induction from E10.5 to E12.5

increased lung tumor incidence ( J:204282 )

• one day following doxycycline administration, adult mutants exhibit formation of small nodules (epithelial clusters) on the lung surface

• papillary adenoma and papillary adenocarcinoma develop in mice treated with doxycycline for 4 and 8 days, respectively

• small tumor nodules and large tumor nodules persist in the lungs of mutants treated with doxycycline for 2-4 days followed by 1 month of doxycycline and in mutants treated with doxycycline for 2 weeks followed by 9 and 18 weeks of withdrawal, respectively

increased lung adenoma incidence ( J:204282 )

• after 4 days of doxycycline induction, nodules are histologically consistent with papillary adenoma

increased lung adenocarcinoma incidence ( J:204282 )

• after 8 days of doxycycline induction, the cells forming papillary structures become atypical with larger and hyperchromatic nuclei, consistent with papillary adenocarcinoma

abnormal branching involved in lung morphogenesis ( J:224791 )

• lungs exhibit reduced branching after doxycycline induction from E10.5 to E12.5

abnormal lung-associated mesenchyme development ( J:224791 )

• lungs exhibit expanded mesenchyme after doxycycline induction from E10.5 to E12.5

abnormal lung epithelium morphology ( J:224791 )

• lungs exhibit dilated epithelial ducts after doxycycline induction from E10.5 to E12.5

respiratory failure ( J:204282 )

• doxycycline treated adults die due to respiratory failure

homeostasis/metabolism

ascites ( J:204282 )

• mutants surviving 4 months of doxycycline induction develop ascites

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
lung cancer		DOID:1324	OMIM:211980 OMIM:608935 OMIM:612571 OMIM:612593 OMIM:614210	J:204282
pleuropulmonary blastoma		DOID:4769		J:224791

Genotype
MGI:3693291

cx29

• Allelic Composition: Tg(SFTPC-rtTA)5Jaw/0; Tg(tetO/CMV-KRAS*G12C)9.1Msmi/0
• Genetic Background: involves: FVB/N

respiratory system

abnormal lung morphology ( J:102839 )

• after 12 days of doxycycline (DOX) treatement, small, hyperplastic lung foci are detected; untreated mice have normal lungs

increased lung adenoma incidence ( J:102839 )

abnormal pulmonary alveolus epithelium morphology ( J:102839 )

• after 5 weeks of DOX treatment, extensive epithelial hyperplasia of alveolar region of lung is observed; untreated mice have normal lungs

abnormal respiratory system physiology ( J:102839 )

abnormal surfactant physiology ( J:102839 )

• alveolar lipoproteinosis is regularly found, indicating abnormal surfactant metabolism

neoplasm

increased tumor incidence ( J:102839 )

• after 3 months treatment, visible macroscopic lesions are found; tumor incidence at 3 months is 55%, with multiplicity of 1.7 tumors/mouse

• lesions are <1mm in size

• early hyperplastic lesions are of alveologenic origin

• at 6 and 9 months DOX treatment, visible lesions increase in number; multiplicity is 10.2 and 12.5 tumors/mouse after 9 and 12 months, lower than Scgb1a1/KRAS bitransgenic mice; treated monotransgenic mice show no incidence

• when DOX treatment was stopped after 9 months, within 2 weeks only 4 tumors are visible on lung surface and by 1 month, no tumors are visible, and with minimal hyperplastic foci microscopically detectable, showing no proliferation (or apoptosis)

increased lung adenoma incidence ( J:102839 )

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
lung benign neoplasm		DOID:3683		J:102839

Genotype
MGI:3586365

cx30

• Allelic Composition: Tg(tetO-Vegfa)90Ala/?; Tg(SFTPC-rtTA)5Jaw/?
• Genetic Background: involves: FVB/N

respiratory system

abnormal lung development ( J:86840 )

• administration of doxycycline to pregnant mother and consequent VEGF-A164 expression in peripheral respiratory epithelial cells of E10.5 to E16.5 embryo caused altered peripheral lung morphogenesis with disrupted vascular pattern formation

Genotype
MGI:3051585

cx31

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

mortality/aging

neonatal lethality, complete penetrance ( J:91723 )

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

respiratory system

abnormal lung lobe morphology ( J:91723 )

• a significant increase in peripheral lung tissue and relatively normal branching morphogenesis are seen with doxycycline treatment; however, lobulation of the lungs is not restored

absent tracheal cartilage rings ( J:91723 )

• doxycycline treatment does not restore tracheal-bronchial cartilaginous ring formation

skeleton

absent tracheal cartilage rings ( J:91723 )

• doxycycline treatment does not restore tracheal-bronchial cartilaginous ring formation

Genotype
MGI:4360917

cx32

• Allelic Composition: Tg(SFTPC-rtTA)5Jaw/0; Tg(tetO-PLAGL2)P3Ysy/0
• Genetic Background: involves: FVB/N

respiratory system

emphysema ( J:152422 )

• doxycycline-treated mice develop centrilobular emphysema and in severe cases such mice exhibit total destruction of an entire lobe

• 90% of doxycycline-treated female mice develop emphysema

abnormal respiratory function ( J:152422 )

• doxycycline-treated female mice exhibit a shift in the inspiratory pressure volume curve to the left indicating an increase in respiratory system compliance compared with wild-type mice

cellular

increased apoptosis ( J:152422 )

• doxycycline-treated mice exhibit an increase in apoptosis in the peripheral airway epithelial cells adjacent to the emphysematous lesions

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
pulmonary emphysema		DOID:9675	OMIM:130700	J:152422

Genotype
MGI:5538517

cx33

• Allelic Composition: Tg(SFTPC-rtTA)5Jaw/0; Tg(tetO-Fgf9,-EGFP)#Dor/0
• Genetic Background: Not Specified

respiratory system

abnormal lung vasculature morphology ( J:107406 )

• doxycycline treated embryos exhibit an extended domain of blood vessels into the expanded lung mesenchyme at E13.5

enlarged lung ( J:107406 )

• beginning at E12.5, doxycycline treated embryos exhibit enlarged lung size

abnormal lung development ( J:107406 )

• doxycycline treated embryos exhibit increased luminal space, fewer epithelial airways and a wide band of mesenchyme separating epithelial ducts at E14.5

abnormal branching involved in lung morphogenesis ( J:107406 )

• doxycycline treated embryos exhibit a reduction in epithelial branching at E11.5 and E12.5

• beginning at E12.5, doxycycline treated embryos exhibit an arrest in branching and luminal dilation

abnormal lung-associated mesenchyme development ( J:107406 )

• doxycycline treated embryos exhibit a large mesenchymal expansion in the lungs at E11.5 and E12.5

abnormal lung epithelium morphology ( J:107406 )

• doxycycline treated embryos show an absence of smooth muscle in the sub-epithelial compartment of lungs at E14.5, although it is present surrounding large blood vessels

cardiovascular system

abnormal lung vasculature morphology ( J:107406 )

• doxycycline treated embryos exhibit an extended domain of blood vessels into the expanded lung mesenchyme at E13.5

growth/size/body

enlarged lung ( J:107406 )

• beginning at E12.5, doxycycline treated embryos exhibit enlarged lung size

Genotype
MGI:5557986

cx34

• Allelic Composition: Gt(ROSA)26Sor^{tm1(tetO-Sox9)Msan}/Gt(ROSA)26Sor⁺; Tg(SFTPC-rtTA)5Jaw/0
• Genetic Background: Not Specified

mortality/aging

perinatal lethality, complete penetrance ( J:202984 )

• when dox treatment was started at E15.5, all 3 double mutants died at birth

respiratory system

abnormal pulmonary alveolus epithelium morphology ( J:202984 )

• in dox treated mice, distal epithelium remains columnar failing to undergo the columnar to squamous transition

cellular

abnormal cell differentiation ( J:202984 )

• when dox treatment is started at E9.5 or E15.5, terminal differentiation of airway cells is inhibited and all differentiated cells are Sox9-negative

Genotype
MGI:4946284

cx35

• Allelic Composition: Tg(SFTPC-rtTA)5Jaw/0; Tg(tetO-MYC)36Bop/0
• Genetic Background: Not Specified

mortality/aging

premature death ( J:169920 )

• mice fed a diet supplemented with DOX to stimulate transactivating function of the rtTA protein and induce MYC expression exhibit reduced lifespan

• treatment of non-DOX treated mutants with the mutagen N-methyl-N-nitrosourea (MNU) accelerates the rate of demise

respiratory system

increased lung tumor incidence ( J:169920 )

• 100% of tumors show activating Kras mutations

increased lung adenoma incidence ( J:169920 )

• mice treated with DOX develop papillary adenomas

increased lung adenocarcinoma incidence ( J:169920 )

• 31.6% penetrance of adenocarcionomas in untreated mice and 57.9% penetrance in DOX treated mice

abnormal pulmonary alveolar system morphology ( J:169920 )

• mice treated with DOX develop alveolar hyperplasia

• alveolar hyperplasia forms as clusters of cells that expand the alveolar septa, reaches a maximum after 4 days of DOX treatment and then resolves due to apoptosis of the hyperplastic cells

neoplasm

increased metastatic potential ( J:169920 )

• 5.9% of DOX treated mice exhibit metastases

increased lung tumor incidence ( J:169920 )

• 100% of tumors show activating Kras mutations

increased lung adenoma incidence ( J:169920 )

• mice treated with DOX develop papillary adenomas

increased lung adenocarcinoma incidence ( J:169920 )

• 31.6% penetrance of adenocarcionomas in untreated mice and 57.9% penetrance in DOX treated mice

decreased tumor incidence ( J:169920 )

• mutants treated with DOX and then MNU have significantly lower number of tumors compared to mutagenized mice not treated with DOX