Phenotypes associated with this allele

• Allele Symbol: Tg(tetO-DTA)1Gfi
• Allele Name: transgene insertion 1, Glenn I Fishman
• Allele ID: MGI:3767624
• Summary: 4 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
cn1	Tg(CAG-Bgeo/ALPP)1Lbe/0 Tg(Ins2-cre/ERT)1Dam/0 Tg(Ins2-rtTA)2Efr/0 Tg(tetO-DTA)1Gfi/0	involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA	MGI:3770687
cx2	Tg(HCRT-tTA)1Ahky/0 Tg(tetO-DTA)1Gfi/0	B6.Cg-Tg(HCRT-tTA)1Ahky Tg(tetO-DTA)1Gfi	MGI:5582929
cx3	Tg(Myh6-tTA)6Smbf/0 Tg(tetO-DTA)1Gfi/0	involves: C57BL/6 * CBA	MGI:3767677
cx4	Tg(Ins2-rtTA)2Efr/0 Tg(tetO-DTA)1Gfi/0	involves: C57BL/6 * CBA	MGI:3770688

Genotype
MGI:3770687

cn1

• Allelic Composition: Tg(CAG-Bgeo/ALPP)1Lbe/0; Tg(Ins2-cre/ERT)1Dam/0; Tg(Ins2-rtTA)2Efr/0; Tg(tetO-DTA)1Gfi/0
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA

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

endocrine/exocrine glands

increased pancreatic beta cell number ( J:127412 )

• tamoxifen injections during last 10 days of doxycycline treatment labels surviving beta cells with human placental alkaline phosphatase; labeling results indicate that majority or all regenerated beta cells are derived from surviving beta cells, rather than from non-beta cells or stem cells

homeostasis/metabolism

hyperglycemia ( J:127412 )

• treatment of newborn mice with doxycycline for 45 days results in diabetes development

Genotype
MGI:5582929

cx2

• Allelic Composition: Tg(HCRT-tTA)1Ahky/0; Tg(tetO-DTA)1Gfi/0
• Genetic Background: B6.Cg-Tg(HCRT-tTA)1Ahky Tg(tetO-DTA)1Gfi

behavior/neurological

increased fluid intake ( J:211045 )

• water intake is decreased by 4 days after DOX removal

decreased locomotor activity ( J:211045 )

• mice become hypoactive after DOX removal with a decrease in spontaneous activity evident in the light period by 1 week after DOX removal and in the dark period by 3 weeks after DOX removal

abnormal sleep pattern ( J:211045 )

• at 13 weeks of DOX removal, sleep/wake fragmentation is greatly increased

• during the dark period, the total time spend in wakefulness is reduced from 3 to 10 weeks after DOX removal

• at 1 week after DOX removal, transition frequency from wakefulness to slow-wave sleep is increased and this is further increased 4 weeks after DOX removal

decreased frequency of paradoxical sleep ( J:211045 )

• the total time spent in REM sleep is decreased during the light period after 2 weeks of DOX removal and a trend toward reduced REM sleep is seen during the dark period

fragmentation of sleep/wake states ( J:211045 )

• at one week after DOX removal, mice show fragmentation of wakefulness particularly in the early dark period

• the transition frequency between sleep/wake states is increased during the dark period between 1 and 13 weeks after DOX removal, but not in the light period

narcolepsy ( J:211045 )

• at 13 weeks of DOX removal, sleep/wake fragmentation and cataplexy bout frequency are greatly increased, indicators of narcolepsy

• increase in cataplexy frequency is followed by a decrease in transitions to REM sleep

hematopoietic system

increased microglial cell activation ( J:211045 )

• IbaI-positive microglial cell number is increased in the lateral hypothalamic area by 2 weeks after DOX removal, indicating microglial cell activation

immune system

increased microglial cell activation ( J:211045 )

• IbaI-positive microglial cell number is increased in the lateral hypothalamic area by 2 weeks after DOX removal, indicating microglial cell activation

muscle

abnormal muscle physiology ( J:211045 )

• cataplexy is seen as early as 2 weeks after DOX removal in both the dark and light periods and bout frequency increases from 2 to 11 weeks after DOX removal

• the time spent in cataplexy increases after 3 weeks of DOX removal during both the dark and the light periods

• mice kept on DOX-free chow from birth show lower number of cataplexy bouts than mice kept on DOX chow from birth and then DOX withdrawal for 13 weeks, indicating that ablation of orexin neurons in adulthood induces much more severe cataplexy episodes than ablation from birth

• cataplexy bout frequency is greater during the dark period and highest during the first half of the dark period and bout frequency tends to increase during the last 12 hours of light period

• cataplexy appears when about 95% of orexin neurons are lost

• mice fed chocolate after DOX removal at the beginning of the dark period show an increase in cataplexy bouts

nervous system

increased microglial cell activation ( J:211045 )

• IbaI-positive microglial cell number is increased in the lateral hypothalamic area by 2 weeks after DOX removal, indicating microglial cell activation

neuron degeneration ( J:211045 )

• severe degeneration of orexin neurons is seen at 12 weeks of age in mice fed a DOX-free chow from birth

• mice raised on DOX chow show a decrease in the number of orexin neurons in the hypothalamus following doxycycline (DOX) removal such that by 2 weeks after DOX removal, about 95% of the orexin neurons are lost and by 11 weeks after DOX removal, orexin neurons decrease further to 1% of controls

• the number of orexin neurons rostral-caudally decreases uniformly after DOX removal, however, they decrease faster in the lateral hypothalamus than the medial population

• orexin neuron nerve endings in terminal fields in the locus ceruleus and dorsal raphe are decreased after DOX removal

• ablation of orexin neurons is arrested by DOX restoration and magnitude of neuron ablation is dependent on the duration of DOX removal

• however, the number of noradrenergic neurons, serotonergic neurons, and melanin-concentrating hormone-positive neuron are unaffected

growth/size/body

increased body weight ( J:211045 )

• body weight begins to increase shortly after DOX removal and is higher by 2 weeks after DOX removal, despite unaltered food consumption

homeostasis/metabolism

increased circulating insulin level ( J:211045 )

• insulin concentrations increase in mice at 4 weeks after DOX removal

increased circulating leptin level ( J:211045 )

• leptin concentrations increase in mice at 4 weeks after DOX removal

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
narcolepsy		DOID:8986	OMIM:161400 OMIM:605841 OMIM:609039 OMIM:612417 OMIM:612851 OMIM:614223 OMIM:614250	J:211045 , J:211046

Genotype
MGI:3767677

cx3

• Allelic Composition: Tg(Myh6-tTA)6Smbf/0; Tg(tetO-DTA)1Gfi/0
• Genetic Background: involves: C57BL/6 * CBA

Cardiac fibrosis and ventricle dilatation in Tg(Myh6-tTA)6Smbf/0 Tg(tetO-DTA)1Gfi/0 mice

mortality/aging

premature death ( J:128617 )

• when Tc treatment is withdrawn after birth, mortality results with median survival time of 37 days (earliest time of death is 12 days after withdrawal of Tc, latest death is 77 days); death occurs suddenly with no indication of illness

lethality throughout fetal growth and development, complete penetrance ( J:128617 )

• in absence of maternal supplementation with tetracycline (Tc) during gestation, no binary (or double) transgenic offspring are born, whereas gestational or perinatal suppressive Tc treatment results in Mendelian numbers of binary offspring (22%)

• genotypic analysis at times throughout gestation show that death of double transgenic embryos occurs between 10.5 days post conception (dpc) and fetal day 19

embryonic lethality during organogenesis, incomplete penetrance ( J:128617 )

• in absence of maternal supplementation with tetracycline (Tc) during gestation, no binary (or double) transgenic offspring are born, whereas gestational or perinatal suppressive Tc treatment results in Mendelian numbers of binary offspring (22%)

• genotypic analysis at times throughout gestation show that death of double transgenic embryos occurs between 10.5 days post conception (dpc) and fetal day 19

cardiovascular system

decreased myocardial fiber number ( J:128617 )

• hearts show evidence of mild to severe myocyte loss

abnormal heart atrium morphology ( J:128617 )

• atrial tissue destruction is seen in some hearts

abnormal heart ventricle morphology ( J:128617 )

• ventricles show patchy fibrosis following Tc withdrawal

dilated heart ventricle ( J:128617 )

• in some hearts, prominent ventricular dilatation is observed following Tc withdrawal

cardiac fibrosis ( J:128617 )

• ventricles show mild patchy fibrosis to severe fibrosis following Tc withdrawal

ventricular tachycardia ( J:128617 )

• at 1 month after Tc withdrawal, most isolated-perfused hearts display either spontaneous or inducible ventricular tachycardia, including both sustained and nonsustained runs of ventricular tachycardia with some episodes lasting

irregular heartbeat ( J:128617 )

• following Tc withdrawal, a variety of arrhythmias are detected in double transgenic mice which show increased propensity to develop reentrant tachycardia, including atrial fibrillation, pauses, and complex ventricular ectopy such as runs of ventricular tachycardia

• majority of even mildly diseased hearts are arrhythmogenic

atrial fibrillation ( J:128617 )

• following tetracycline withdrawal, atrial fibrillation occurs in some mice

abnormal impulse conducting system conduction ( J:128617 )

• at 1 month after tetracycline withdrawal, a subset of isolated-perfused hearts display markedly disturbed activation profiles, with either disorganized conduction or evidence of block during pacing

• majority of even mildly diseased hearts are arrhythmogenic

muscle

decreased myocardial fiber number ( J:128617 )

• hearts show evidence of mild to severe myocyte loss

increased cardiomyocyte apoptosis ( J:128617 )

• some hearts display severe cell loss following tetracycline withdrawal

homeostasis/metabolism

abnormal atrial thrombosis ( J:128617 )

• mural thrombus formation is prominent in atrial tissue in some animals following Tc withdrawal

cellular

increased cardiomyocyte apoptosis ( J:128617 )

• some hearts display severe cell loss following tetracycline withdrawal

Genotype
MGI:3770688

cx4

• Allelic Composition: Tg(Ins2-rtTA)2Efr/0; Tg(tetO-DTA)1Gfi/0
• Genetic Background: involves: C57BL/6 * CBA

endocrine/exocrine glands

endocrine/exocrine gland phenotype ( J:127412 )

N • average size of regenerating beta cells is same as original cells

abnormal pancreas morphology ( J:127412 )

• pancreatic insulin content is reduced by ~85%; after doxycycline withdrawal, pancreatic insulin level return to near control levels

abnormal pancreatic beta cell morphology ( J:127412 )

• frequency of insulin-positive, glucagons-positive beta cells increases from 1:5500 in controls to 1:1000 beta cells in diabetic transgenic mice

• permitting doxycycline-treated mice to recover in presence of immunosupressants Sirolimus and Tacrolimus (SirTac) significantly reduces beta cell proliferation and beta cell mass does not increase as it does in absence of immunosupressants; blood glucose levels in treated mice fail to normalize as they do in controls treated with SirTac

decreased pancreatic beta cell number ( J:127412 )

• 70-80% of beta cells are lost in doxycycline-treated 5-week old double-transgenic mice relative to controls

• similar results are obtained when beta cells are ablated between birth and five weeks of age; beta cell mass normalizes within ~15 weeks of doxycycline withdrawal

increased pancreatic beta cell number ( J:127412 )

• rate of beta cell apoptosis in recovering mice is not different from controls, but beta cell proliferation is increased 2-3-fold within 48 hours of onset of beta cell ablation; this increased proliferation rate is maintained for several weeks

disorganized pancreatic islets ( J:127412 )

• treatment of four-week old mice with doxycycline for 1 week results in severely disrupted islet architecture with non-beta cells at the core of shriveled islets rather than beta cells

• after withdrawal of doxycycline, normalization of islet architecture occurs in ~90% of islets

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:127412 )

N • peripheral insulin sensitivity after beta cell regeneration is similar to controls after doxycycline withdrawal, beta cell mass in transgenic mice increases to levels comparable to wild-type

increased circulating glucose level ( J:127412 )

• blood glucose levels of treated mice are elevated to 300-600 mg/dl making the mice overtly diabetic; after withdrawal of doxycycline, blood glucose levels return to normal level

• mice that showed severe, chronic or adult-onset (starting at 4 months) hyperglycemia spontaneously normalized blood glucose levels and beta-cell mass after doxycycline withdrawal

hyperglycemia ( J:127412 )

• blood glucose levels are elevated to 300-600 mg/dl; after doxycycline withdrawal, remission of hyperglycemia occurs such that fed and fasting glucose levels normalize

• mice that showed severe, chronic or adult-onset (starting at 4 months) hyperglycemia spontaneously normalized blood glucose levels and beta-cell mass after doxycycline withdrawal

improved glucose tolerance ( J:127412 )

• after more than 8 months without doxycycline, glucose tolerance starts to recover

• similar results are obtained when beta cells are ablated between birth and five weeks of age; beta cell mass normalizes within ~15 weeks of doxycycline withdrawal

• mice that showed severe, chronic or adult-onset (starting at 4 months) hyperglycemia spontaneously normalized blood glucose levels and beta-cell mass after doxycycline withdrawal

cellular

increased apoptosis ( J:127412 )

• widespread pancreatic beta cell apoptosis is seen within 48 hours of doxycycline treatment of double-transgenic mice, but no apoptosis is observed in single transgenic littermates