Phenotypes associated with this allele

• Allele Symbol: Tle3^tm1.1Pton
• Allele Name: targeted mutation 1.1, Peter Tontonoz
• Allele ID: MGI:5505553
• Summary: 4 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
cn1	Tle3^tm1.1Pton/Tle3^tm1.1Pton Tle4^tm1.1Dasw/Tle4^tm1.1Dasw Tg(Pdx1-cre)6Tuv/0	involves: 129P2/OlaHsd * 129S6/SvEvTac * C57BL/6 * FVB/N	MGI:7432863
cn2	Tle3^tm1.1Pton/Tle3^tm1.1Pton Tg(Pdx1-cre)6Tuv/0	involves: 129P2/OlaHsd * C57BL/6 * FVB/N	MGI:7432861
cn3	Tle2^tm1(KOMP)Vlcg/Tle2^tm1(KOMP)Vlcg Tle3^tm1.1Pton/Tle3^tm1.1Pton Tg(Pdx1-cre)6Tuv/0	involves: 129P2/OlaHsd * C57BL/6 * FVB/N	MGI:7859479
cn4	Tle3^tm1.1Pton/Tle3^tm1.1Pton Tg(Adipoq-cre)1Evdr/0	involves: 129P2/OlaHsd * C57BL/6J * FVB/NJ	MGI:5505584

Genotype
MGI:7432863

cn1

• Allelic Composition: Tle3^tm1.1Pton/Tle3^tm1.1Pton; Tle4^tm1.1Dasw/Tle4^tm1.1Dasw; Tg(Pdx1-cre)6Tuv/0
• Genetic Background: involves: 129P2/OlaHsd * 129S6/SvEvTac * C57BL/6 * FVB/N

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

mortality/aging

postnatal lethality, incomplete penetrance ( J:307817 )

• although born at normal Mendelian ratios, fewer double knockout mice are recovered at weaning (12% vs expected 25%), suggesting early postnatal lethality

homeostasis/metabolism

hyperglycemia ( J:307817 )

• at 4-6 weeks of age, double knockout mice are extremely hyperglycemic with significantly higher ad libitum blood glucose levels than Tle3 single knockout mice

• blood glucose levels are already elevated at P2, indicating perinatal hyperglycemia

impaired glucose tolerance ( J:307817 )

• at 4-6 weeks of age, double knockout mice show more severe glucose intolerance than Tle3 single knockout mice

endocrine/exocrine glands

decreased pancreatic beta cell proliferation ( J:307817 )

• the percentage of proliferating Ki67+ cells in INS+ cells is significantly decreased at E16.5 and P2

• however, no increase in beta cell apoptosis is detected by TUNEL staining

abnormal pancreatic islet morphology ( J:307817 )

• immunofluorescent staining of islet hormones shows a small number of bihormonal cells co-expressing insulin and somatostatin (INS+/SST+) cells at 4 weeks of age, similar to those in Tle3 single knockout mice

• however, no cells co-expressing insulin and glucagon (INS+/GCG+) are observed

decreased pancreatic beta cell mass ( J:307817 )

• double knockout mice show a significantly smaller pancreatic beta cell (INS+) area at E16.5 and P2, with no apparent changes in the SST+ or GCG+ cell area

• however, the number of NEUROG3+ cells is unchanged at E16.5, indicating a normal endocrine progenitor pool

decreased pancreatic beta cell number ( J:307817 )

• immunofluorescence staining of islet hormone expression shows a significant decrease in the number of INS+ beta cells at P2, with no apparent change in somatostatin (SST+) or glucagon (GCG+) expressing cells

disorganized pancreatic islets ( J:307817 )

• pancreatic islets exhibit disorganized morphology at 4 weeks of age

abnormal pancreas development ( J:307817 )

• at E18.5, pancreata show severe dysregulation of the pancreas gene program with ectopic expression of canonical liver genes and Foxa1 (a master regulator of the liver program)

• Foxa1 mRNA expression is increased 8.7-fold at E18.5 while ectopic FOXA1 protein is detected in the pancreas at E12.5, P2 and 6 weeks of age

• Neurod1 (an essential beta cell transcription factor and predicted target of Foxa1) and many of the direct Neurod1 target genes are significantly downregulated at E18.5

abnormal pancreatic beta cell differentiation ( J:307817 )

• although pancreatic beta (INS+) cells are specified by E16.5, a significant decrease in beta cell mass is noted at E16.5 and P2

• at P2, beta cells lack expression of NEUROD1, a transcription factor required for beta cell proliferation, survival and maturation

cellular

abnormal pancreatic beta cell differentiation ( J:307817 )

• although pancreatic beta (INS+) cells are specified by E16.5, a significant decrease in beta cell mass is noted at E16.5 and P2

• at P2, beta cells lack expression of NEUROD1, a transcription factor required for beta cell proliferation, survival and maturation

decreased pancreatic beta cell proliferation ( J:307817 )

• the percentage of proliferating Ki67+ cells in INS+ cells is significantly decreased at E16.5 and P2

• however, no increase in beta cell apoptosis is detected by TUNEL staining

growth/size/body

growth/size/body region phenotype ( J:307817 )

N • double knockout neonates exhibit normal body weight at P2; those surviving to weaning show normal body weight at 4-6 weeks of age

Genotype
MGI:7432861

cn2

• Allelic Composition: Tle3^tm1.1Pton/Tle3^tm1.1Pton; Tg(Pdx1-cre)6Tuv/0
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6 * FVB/N

homeostasis/metabolism

decreased insulin secretion ( J:307817 )

• pancreatic islets isolated from 12-week-old mice show a significant decrease in intracellular insulin content

hyperglycemia ( J:307817 )

• mice are hyperglycemic with significantly increased ad libitum blood glucose levels at all time points between P0 and 12 months of age

impaired glucose tolerance ( J:307817 )

• mice are glucose intolerant at 6 weeks of age

endocrine/exocrine glands

abnormal pancreatic islet morphology ( J:307817 )

• immunofluorescent staining of islet hormones shows a small number of bihormonal cells co-expressing insulin and somatostatin (INS+/SST+) at 6 weeks of age

• however, no visible defects in delamination of the endocrine population are noted at P0

decreased pancreatic beta cell number ( J:307817 )

• pancreatic islets isolated from 6-week-old mice show an obvious decrease in the number of INS+ beta cells with no apparent defect in the other endocrine cell types

• however, E18.5 islets are largely normal with only a trend towards decreased beta cell numbers and no defects in the number of non-beta endocrine cells or levels of the other endocrine hormones

abnormal endocrine pancreas physiology ( J:307817 )

• at E18.5, pancreata show a small, but significant, decrease in Ins1 (insulin I), Ins2 (insulin II) and Gcg (glucagon) mRNA expression

• islets isolated from 8-week-old mice show a 3-fold increase in mRNA expression of Tle4 (Grg4), but no change in Tle1 (Grg1), suggesting that Tle4 upregulation is compensating for the loss of Tle3 (Grg3) and preventing a more severe pancreas phenotype

decreased insulin secretion ( J:307817 )

• pancreatic islets isolated from 12-week-old mice show a significant decrease in intracellular insulin content

growth/size/body

growth/size/body region phenotype ( J:307817 )

N • mice exhibit normal body weight at 4-6 weeks of age

Genotype
MGI:7859479

cn3

• Allelic Composition: Tle2^{tm1(KOMP)Vlcg}/Tle2^{tm1(KOMP)Vlcg}; Tle3^tm1.1Pton/Tle3^tm1.1Pton; Tg(Pdx1-cre)6Tuv/0
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6 * FVB/N

homeostasis/metabolism

impaired glucose tolerance ( J:307817 )

• double knockout mice are glucose intolerant at 8 weeks of age, with no significant worsening of the Tle3 (Grg3) single knockout phenotype

endocrine/exocrine glands

decreased pancreatic beta cell number ( J:307817 )

• pancreatic islets isolated from 7-mo-old double knockout mice show an obvious decrease in the number of INS+ beta cells that is similar to that in Tle3 (Grg3) single knockout mice

Genotype
MGI:5505584

cn4

• Allelic Composition: Tle3^tm1.1Pton/Tle3^tm1.1Pton; Tg(Adipoq-cre)1Evdr/0
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6J * FVB/NJ

adipose tissue

abnormal brown adipose tissue morphology ( J:198134 )

• browner in color than in control mice

abnormal brown fat cell morphology ( J:198134 )

• increase in cells with multilocular lipid droplets characteristic of young brown adipose tissue

abnormal inguinal fat pad morphology ( J:198134 )

• evidence of browning with increased numbers of cells with multilocular lipid droplets

homeostasis/metabolism

decreased susceptibility to induced hypothermia ( J:198134 )

• improved ability to respond to cold exposure

increased core body temperature ( J:198134 )

• in respond to cold exposure

increased energy expenditure ( J:198134 )

• when housed in metabolic cages

behavior/neurological

behavior/neurological phenotype ( J:198134 )

N • mice exhibit normal activity level and food intake