Phenotypes associated with this allele

• Allele Symbol: Pdx1^tm1Ted
• Allele Name: targeted mutation 1, Thomas Edlund
• Allele ID: MGI:2152755
• Summary: 3 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Pdx1^tm1Ted/Pdx1^tm1Ted	involves: 129P2/OlaHsd	MGI:2173182
ht2	Pdx1^tm1Ted/Pdx1^+	involves: 129P2/OlaHsd	MGI:3531547
cn3	Insr^tm1Khn/Insr^tm1Khn Pdx1^tm1Ted/Pdx1^+ Speer6-ps1^Tg(Alb-cre)21Mgn/Speer6-ps1^+	involves: 129S4/SvJae * C57BL/6 * DBA/2	MGI:3583116

Genotype
MGI:2173182

hm1

• Allelic Composition: Pdx1^tm1Ted/Pdx1^tm1Ted
• Genetic Background: involves: 129P2/OlaHsd

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

mortality/aging

postnatal lethality, complete penetrance ( J:20779 )

• all homozygotes die within a few days after birth

digestive/alimentary system

abnormal small intestine placement ( J:20779 )

• mutant intestines are of normal length and show no overt abnormalities; however, the loops of the small intestine are positioned slightly differently in the abdomen relative to wild-type

endocrine/exocrine glands

abnormal pancreas development ( J:33133 )

• at E10, the mutant dorsal pancreatic epithelium forms a bud but then becomes growth arrested and fails to lobulate

• at E11 and E12, the dorsal bud is significantly smaller than wild-type; the remaining, growth-arrested bud remains unbranched

• at E10-E12, the mutant ventral pancreatic bud appears to be absent

• although the mutant pancreatic epithelium is growth-arrested, the dorsal pancreatic mesenchyme grows and develops normally, with a morphologically normal, bud-like shape found at its normal position

• notably, the mutant mesenchyme is functionally active and able to promote morphogenesis and differentiation of pancreatic epithelium when recombined in vitro; in contrast, mutant pancreatic epithelium cannot be rescued by adding wild-type mesenchyme

• at E13.5, the mutant dorsal pancreatic mesenchyme is present as a "hollow pocket" that can be dissected away from the stomach and duodenum; in wild-type E13-E14 embryos, this mesenchymal pocket is filled by pancreatic epithelium

• at E10, early glucagon cells are present but are unable to proliferate and/or differentiate; a few early insulin cells are present at E10, but are no longer detectable at E13, in the absence of increased apoptosis

absent pancreas ( J:20779 )

• homozygotes completely lack a pancreas; no pancreatic tissue is present in E15.5 embryos or neonates

• notably, the duodenum (from which the pancreas develops) has a normal C-shaped form; no ectopic expression of insulin and pancreatic amylase is detected in the developing duodenum

• the pancreatic duct is missing; however, the common bile duct is present, indicating that apart from the lack of pancreas, the duodenal tract is normally developed

growth/size/body

decreased body size ( J:20779 )

• homozygotes appear morphologically normal but are slightly smaller than wild-type and heterozygous littermates: on average, ~80% for newborn pups and ~60% for 2-day-old pups

homeostasis/metabolism

increased circulating glucose level ( J:20779 )

• pups that are able to feed and live for more than 2 days exhibit elevated glucose levels, suggesting that the cause of death is partly due to insulin deficiency

immune system

immune system phenotype ( J:20779 )

N • mutant spleens are of normal weight and show no apparent abnormalities relative to wild-type

liver/biliary system

liver/biliary system phenotype ( J:20779 )

N • mutant livers are of normal weight and show no apparent abnormalities relative to wild-type

Genotype
MGI:3531547

ht2

• Allelic Composition: Pdx1^tm1Ted/Pdx1⁺
• Genetic Background: involves: 129P2/OlaHsd

cellular

abnormal pancreatic islet cell apoptosis ( J:82969 )

• however, no significant differences are noted at high glucose (25 mM) or Ca2+ stress

• isolated heterozygous islets are significantly more susceptible to apoptosis at basal glucose concentrations than wild-type islets

abnormal pancreatic beta cell apoptosis ( J:82969 )

• dispersed beta cells are significantly more susceptible to apoptosis at basal glucose concentrations than wild-type islets

• however, no significant differences are noted at high glucose (25 mM) or Ca2+ stress

endocrine/exocrine glands

abnormal pancreatic islet cell apoptosis ( J:82969 )

• isolated heterozygous islets are significantly more susceptible to apoptosis at basal glucose concentrations than wild-type islets

• however, no significant differences are noted at high glucose (25 mM) or Ca2+ stress

abnormal pancreatic beta cell apoptosis ( J:82969 )

• dispersed beta cells are significantly more susceptible to apoptosis at basal glucose concentrations than wild-type islets

• however, no significant differences are noted at high glucose (25 mM) or Ca2+ stress

abnormal pancreatic islet morphology ( J:82969 )

• islet isolation procedures generate very few islets (always <100) from heterozygotes compared with wild-type mice (almost always >200 islets)

• isolated heterozygous islets appear fragmented and slightly smaller than wild-type

• in vivo, heterozygotes show a striking disruption of islet architecture and expansion of islet microvasculature at 3 months; however, even at 12 months, some heterozygous islets show no signs of damage or apoptosis

• in heterozygotes, islet number fails to increase with age and is ~50% less than wild-type by 12 months

decreased pancreatic beta cell mass ( J:82969 )

• in heterozygotes, beta cell mass fails to increase with age and is ~50% less than wild-type by 12 months

• reduced beta cell mass is mirrored by a lower pancreatic insulin content in older mice and can be explained by a reduced number of functional islets, rather than a reduction in insulin stored in single beta cells

decreased pancreatic islet number ( J:82969 )

small pancreatic islets ( J:82969 )

decreased insulin secretion ( J:82969 )

• perfused pancreata from heterozygous males display attenuated first-phase insulin secretion in response to a stepwise increase in glucose concentration from 5 mM to 20 mM glucose

• mutant pancreata show a reduced insulin release in response to 20 mM KCl; in the continued presence of 26 mM glucose, the large response to 20 mM arginine is also reduced

• insulin secretion in perfusion or static incubation experiments in response to glucose and other secretagogues is similar in islets isolated from heterozygous mutants compared with wild-type littermates

• glucose sensing and islet Ca2+ responses are normal in large, intact heterozygous mutant islets

pancreas inflammation ( J:82969 )

• at 12 months, older heterozygotes exhibit infiltration of lymphocytes (some TUNEL-positive) within or around islets

• immunofluorescent localization of Ki67 nuclear antigen indicates proliferation of lymphocytes within these islets

homeostasis/metabolism

decreased insulin secretion ( J:82969 )

• perfused pancreata from heterozygous males display attenuated first-phase insulin secretion in response to a stepwise increase in glucose concentration from 5 mM to 20 mM glucose

• mutant pancreata show a reduced insulin release in response to 20 mM KCl; in the continued presence of 26 mM glucose, the large response to 20 mM arginine is also reduced

• insulin secretion in perfusion or static incubation experiments in response to glucose and other secretagogues is similar in islets isolated from heterozygous mutants compared with wild-type littermates

• glucose sensing and islet Ca2+ responses are normal in large, intact heterozygous mutant islets

increased circulating glucose level ( J:82969 )

• heterozygous mutant males exhibit significantly elevated blood glucose concentrations relative to wild-type males

• notably, heterozygous females display an attenuated increase in blood glucose levels relative to wild-type

impaired glucose tolerance ( J:48516 , J:82969 )

• heterozygotes exhibit a decline in glucose tolerance with increasing age (J:82969)

immune system

pancreas inflammation ( J:82969 )

• at 12 months, older heterozygotes exhibit infiltration of lymphocytes (some TUNEL-positive) within or around islets

• immunofluorescent localization of Ki67 nuclear antigen indicates proliferation of lymphocytes within these islets

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
maturity-onset diabetes of the young		DOID:0050524	OMIM:606391	J:48516 , J:82969
maturity-onset diabetes of the young type 4		DOID:0111103	OMIM:606392	J:82969

Genotype
MGI:3583116

cn3

• Allelic Composition: Insr^tm1Khn/Insr^tm1Khn; Pdx1^tm1Ted/Pdx1⁺; Speer6-ps1^{Tg(Alb-cre)21Mgn}/Speer6-ps1⁺
• Genetic Background: involves: 129S4/SvJae * C57BL/6 * DBA/2

endocrine/exocrine glands

decreased pancreatic beta cell mass ( J:92861 )

• these mutants fail to exhibit an adaptive islet hyperplastic response to insulin resistance; instead, pancreatic beta cell mass is reduced, and islets appear small with scattered non-beta cells