Tg(tetO-DTA)1Gfi Transgene Detail MGI Mouse (MGI:3767624)

Tg(tetO-DTA)1Gfi
Transgene Detail

Nomenclature

Symbol:	Tg(tetO-DTA)1Gfi
Name:	transgene insertion 1, Glenn I Fishman
MGI ID:	MGI:3767624
Synonyms:	tet-DTA, tetO^DTA/+
Transgene:	Tg(tetO-DTA)1Gfi Location: unknown

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

Show the 1 image(s) involving this allele.

Transgene
origin

Strain of Origin:

(C57BL/6 x CBA)F2

Transgene
description

Transgene Type:	Transgenic (random, expressed)
Mutation:	Insertion
	A transgenic construct was created, containing diphtheria toxin A sequence (DTA) under the control of heptamerized tetracycline operator, tetO sequences fused to a cytomegalovirus minimal promoter. (J:128617)

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Mouse strains and cell lines available from the International Mouse Strain Resource (IMSR)

Carrying this Mutation:

Mouse Strains: 3 strains available Cell Lines: 0 lines available

Phenotype
summary

Phenotype Summary by Mammalian Phenotype terms

(show or hide all annotated terms)

Genotypes are listed in the next section.

Key:

hm	homozygous	ht	heterozygous
cn	conditional genotype	cx	complex: > 1 genome feature
tg	involves transgenes	ot	other: hemizygous, indeterminate,...
N	normal phenotype		expected model not found

Affected Systems	Genotypes:	tg1	tg2	tg3
cardiovascular system			√
increased cardiomyocyte apoptosis			√
decreased myocardial fiber number			√
abnormal heart atrium morphology			√
abnormal heart ventricle morphology			√
dilated heart ventricles			√
cardiac fibrosis			√
ventricular tachycardia			√
irregular heartbeat			√
atrial fibrillation			√
abnormal impulse conducting system conduction			√
		tg1	tg2	tg3
cellular				√
increased apoptosis				√
		tg1	tg2	tg3
digestive/alimentary system		√		√
abnormal pancreas morphology				√
abnormal pancreatic beta cell morphology				√
increased pancreatic beta cell number		√		√
decreased pancreatic beta cell number				√
disorganized pancreatic islets				√
		tg1	tg2	tg3
endocrine/exocrine glands		√		√
endocrine/exocrine glands phenotype				N
abnormal pancreas morphology				√
abnormal pancreatic beta cell morphology				√
increased pancreatic beta cell number		√		√
decreased pancreatic beta cell number				√
disorganized pancreatic islets				√
		tg1	tg2	tg3
homeostasis/metabolism		√	√	√
homeostasis/metabolism phenotype				N
atrial thrombosis			√
increased circulating glucose level				√
hyperglycemia		√		√
improved glucose tolerance				√
		tg1	tg2	tg3
lethality/prenatal-perinatal			√
embryonic lethality during organogenesis			√
		tg1	tg2	tg3
life span/aging			√
premature death			√
		tg1	tg2	tg3
muscle			√
increased cardiomyocyte apoptosis			√
decreased myocardial fiber number			√

Phenotypic
data by
genotype

Phenotypic Data by Genotype

(show or hide all phenotypic details)

Genotype	Allelic Composition	Genetic Background
tg1	Tg(CAG-Bgeo/ALPP)1Lbe/0 Tg(Ins2-cre/Esr1)1Dam/0 Tg(Ins2-rtTA)2Efr/0 Tg(tetO-DTA)1Gfi/0	involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA
digestive/alimentary system 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 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	Allelic Composition	Genetic Background
tg2	Tg(Myh6-tTA)6Smbf/0 Tg(tetO-DTA)1Gfi/0	involves: C57BL/6 * CBA
Cardiac fibrosis and ventricle dilatation in Tg(Myh6-tTA)6Smbf/0 Tg(tetO-DTA)1Gfi/0 mice lethality/prenatal-perinatal embryonic lethality during organogenesis (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 life span/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 cardiovascular system increased cardiomyocyte apoptosis (J:128617) some hearts display severe cell loss following tetracycline withdrawal 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 ventricles (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 increased cardiomyocyte apoptosis (J:128617) some hearts display severe cell loss following tetracycline withdrawal decreased myocardial fiber number (J:128617) hearts show evidence of mild to severe myocyte loss homeostasis/metabolism atrial thrombosis (J:128617) mural thrombus formation is prominent in atrial tissue in some animals following Tc withdrawal
Genotype	Allelic Composition	Genetic Background
tg3	Tg(Ins2-rtTA)2Efr/0 Tg(tetO-DTA)1Gfi/0	involves: C57BL/6 * CBA
endocrine/exocrine glands endocrine/exocrine gland phenotype (J:127412) 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 digestive/alimentary system 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) 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

References

Original:	J:128617 Lee P et al., "Conditional lineage ablation to model human diseases." Proc Natl Acad Sci U S A 1998 Sep 15;95(19):11371-6
All:	3 reference(s)

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