Mouse Genome Informatics
hm1
    Pdx1tm1Ted/Pdx1tm1Ted
involves: 129P2/OlaHsd
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• all homozygotes die within a few days after birth

digestive/alimentary system
• 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
• 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
• 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
• 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
• 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
N
• mutant spleens are of normal weight and show no apparent abnormalities relative to wild-type (J:20779)

liver/biliary system
N
• mutant livers are of normal weight and show no apparent abnormalities relative to wild-type (J:20779)


Mouse Genome Informatics
ht2
    Pdx1tm1Ted/Pdx1+
involves: 129P2/OlaHsd
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
endocrine/exocrine glands
• 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
• 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
• heterozygotes display normal depolarization-evoked single-cell exocytosis and voltage-gated Ca2+ currents in beta cells
• however, isolated heterozygous islets and dispersed beta cells are significantly more susceptible to apoptosis at basal glucose concentrations than wild-type islets; no significant differences are noted at high glucose (25 mM) or Ca2+ stress
• 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
• also, 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
• notably, insulin secretion in perifusion 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 also normal in large, intact heterozygous mutant islets
• 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
• 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
• also, 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
• notably, insulin secretion in perifusion 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 also normal in large, intact heterozygous mutant islets
• 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
• heterozygotes exhibit a decline in glucose tolerance with increasing age (J:82969)

immune system
• 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 Genome Informatics
cn3
    Insrtm1Khn/Insrtm1Khn
Pdx1tm1Ted/Pdx1+
Tg(Alb-cre)21Mgn/0

involves: 129S4/SvJae * C57BL/6 * DBA/2
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
endocrine/exocrine glands
• 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