All Phenotypes Foxo4<tm1Rdp> MGI Mouse

Phenotypes associated with this allele

Jump to	Allelic Composition	Genetic Background	Genotype ID
cn1	Foxo1^tm1Rdp/Foxo1^tm1Rdp Foxo3^tm1Rdp/Foxo3^tm1Rdp Foxo4^tm1Rdp/Foxo4^tm1Rdp Tg(Ins2-cre)23Herr/0	involves: 129S6/SvEvTac * C57BL/6 * C57BL/6J * CBA/J	MGI:5638417
cn2	Foxo1^tm1Rdp/Foxo1^tm1Rdp Foxo4^tm1Rdp/Foxo4^tm1Rdp Tg(Mx1-cre)1Cgn/0	involves: 129S6/SvEvTac * C57BL/6 * CBA * FVB/N	MGI:3706818
cn3	Foxo1^tm1Rdp/Foxo1^tm1Rdp Foxo3^tm1Rdp/Foxo3^tm1Rdp Foxo4^tm1Rdp/Foxo4^tm1Rdp Tg(Mx1-cre)1Cgn/0	involves: 129S6/SvEvTac * C57BL/6 * CBA * FVB/N	MGI:3706822

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

homeostasis/metabolism

abnormal glucose homeostasis ( J:215526 )

• mice show a defect in glucose-dependent insulin secretion that leads to early-onset, mild and moderately progressive diabetes

• mice subjected to hyperglycemic clamps require an approximate 50% lower rate of glucose infusion to maintain steady-state hyperglycemia

decreased insulin secretion ( J:215526 )

• mice are impaired in secreting insulin in response to the ATP-dependent K-channel blocker, glibenclamide, and to the depolarizing agent, I-arginine

• beta cells exhibit reduced calcium-dependent insulin secretion

• purified islets show lower insulin secretion in response to the sulfonylurea glibenclamide, the PKC activator PMA, and the L-type Ca channel activator Bay-K8644

hyperglycemia ( J:215526 )

• mice exhibit hyperglycemia in the fasted, refed, and random-fed states as early as 12 weeks of age

decreased circulating insulin level ( J:215526 )

• mice exhibit lower plasma insulin levels in fasted, refed, and random-fed states, although not significant in the latter state

impaired glucose tolerance ( J:215526 )

• mice show impaired glucose tolerance that worsens progressively with age during intraperitoneal glucose tolerance tests, without changes to peripheral insulin sensitivity

endocrine/exocrine glands

abnormal pancreatic beta cell differentiation ( J:215526 )

• as mice age to 12 months, beta cell dedifferentiation occurs

abnormal pancreatic beta cell physiology ( J:215526 )

• beta cells are metabolically inflexible such that they preferentially utilize lipids rather than carbohydrates as an energy source resulting in impaired ATP generation and reduced calcium-dependent insulin secretion

• glucose oxidation to carbon dioxide is impaired by about 50% in islets at most glucose concentrations

• palmitate oxidation by islets in the presence of basal glucose is 2-fold higher and nearly 2.5-fold higher in high glucose

• glycerolipid synthesis of islets is normal at low glucose concentrations but fails to increase at elevated glucose concentrations, resulting in lower conversion of palmitate into diacylglycerides and triglycerides indicating that beta cells appear to be locked in a lipid oxidative state

• membrane depolarization-induced calcium influx in response to rising glucose concentrations is lower in beta cells

decreased insulin secretion ( J:215526 )

• mice are impaired in secreting insulin in response to the ATP-dependent K-channel blocker, glibenclamide, and to the depolarizing agent, I-arginine

• beta cells exhibit reduced calcium-dependent insulin secretion

• purified islets show lower insulin secretion in response to the sulfonylurea glibenclamide, the PKC activator PMA, and the L-type Ca channel activator Bay-K8644

cellular

abnormal pancreatic beta cell differentiation ( J:215526 )

• as mice age to 12 months, beta cell dedifferentiation occurs

abnormal mitochondrial physiology ( J:215526 )

• islets show a decrease in glucose-induced oxygen consumption

• raising glucose levels does not increase ATP turnover in purified islets as in control islets

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
maturity-onset diabetes of the young		DOID:0050524	OMIM:606391	J:215526

Allelic Composition	Foxo1^tm1Rdp/Foxo1^tm1Rdp Foxo4^tm1Rdp/Foxo4^tm1Rdp Tg(Mx1-cre)1Cgn/0
Genetic Background	involves: 129S6/SvEvTac * C57BL/6 * CBA * FVB/N

Find Mice

Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Foxo1^tm1Rdp mutation (2 available); any Foxo1 mutation (32 available)
Foxo4^tm1Rdp mutation (1 available); any Foxo4 mutation (15 available)
Tg(Mx1-cre)1Cgn mutation (7 available)

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

mortality/aging

premature death ( J:118179 )

• development of hemangiomas leads to premature death starting to significant levels at ~50 weeks of age with induced cre expression

neoplasm

increased hamartoma incidence ( J:118179 )

• mice develop an age-progressive hamarotomatous phenotype with cre expression

increased hemangioma incidence ( J:118179 )

• females display mild hemangiomas, most exaggerated in the uterus and occasionally other tissues by 6-8 weeks after induction of cre expression with poly(I:C)

increased hepatic hemangioma incidence ( J:118179 )

• discrete liver hemangiomas and occasionally angiosarcomas are observed in aged mice (5/7 in mice that died at 58-86 weeks and 2/2 examined at 96-98 weeks)

increased hemangiosarcoma incidence ( J:118179 )

• in ~9% of mice, lesions progress to lethal angiosarcomas

liver/biliary system

increased hepatic hemangioma incidence ( J:118179 )

• discrete liver hemangiomas and occasionally angiosarcomas are observed in aged mice (5/7 in mice that died at 58-86 weeks and 2/2 examined at 96-98 weeks)

Allelic Composition	Foxo1^tm1Rdp/Foxo1^tm1Rdp Foxo3^tm1Rdp/Foxo3^tm1Rdp Foxo4^tm1Rdp/Foxo4^tm1Rdp Tg(Mx1-cre)1Cgn/0
Genetic Background	involves: 129S6/SvEvTac * C57BL/6 * CBA * FVB/N

Find Mice

Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Foxo1^tm1Rdp mutation (2 available); any Foxo1 mutation (32 available)
Foxo3^tm1Rdp mutation (1 available); any Foxo3 mutation (51 available)
Foxo4^tm1Rdp mutation (1 available); any Foxo4 mutation (15 available)
Tg(Mx1-cre)1Cgn mutation (7 available)

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

mortality/aging

premature death ( J:118179 )

• induced mice start to show significant mortality starting at ~22 weeks with ~90% mortality by 75 weeks of age

neoplasm

increased T cell derived lymphoma incidence ( J:118179 )

• by 19-30 weeks, after cre induction, mice develop aggressive CD8+ CD4+ thymic lymphomas that spread to the spleen, lymph nodes and liver

• wild-type mice and all other conditional genotypes examined here do not show any lymphomas up to 100 weeks of age

increased hamartoma incidence ( J:118179 )

• mice develop an age-progressive hamarotomatous phenotype with cre expression

increased hemangioma incidence ( J:118179 )

• mice show widespread development of hemangiomas, most exaggerated in uterus and visible by 6-8 weeks

• lesions (usually benign) progress greatly by 30-40 weeks, with affected animals showing massive hemangiomas with intraluminal blood and thrombi in skeletal muscle, abdominal wall, liver, adrenal glands, bone marrow, omentum, lymph nodes, and skin

increased hemangiosarcoma incidence ( J:118179 )

• in ~9% of mice, lesions progress to lethal angiosarcomas

endocrine/exocrine glands

increased T cell derived lymphoma incidence ( J:118179 )

• by 19-30 weeks, after cre induction, mice develop aggressive CD8+ CD4+ thymic lymphomas that spread to the spleen, lymph nodes and liver

• wild-type mice and all other conditional genotypes examined here do not show any lymphomas up to 100 weeks of age

hematopoietic system

increased T cell derived lymphoma incidence ( J:118179 )

• by 19-30 weeks, after cre induction, mice develop aggressive CD8+ CD4+ thymic lymphomas that spread to the spleen, lymph nodes and liver

• wild-type mice and all other conditional genotypes examined here do not show any lymphomas up to 100 weeks of age

immune system

increased T cell derived lymphoma incidence ( J:118179 )

• by 19-30 weeks, after cre induction, mice develop aggressive CD8+ CD4+ thymic lymphomas that spread to the spleen, lymph nodes and liver

• wild-type mice and all other conditional genotypes examined here do not show any lymphomas up to 100 weeks of age

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