Analysis Tools
mortality/aging
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• although born at normal Mendelian ratios, fewer double knockout mice are recovered at weaning (12% vs expected 25%), suggesting early postnatal lethality
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homeostasis/metabolism
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• 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
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• at 4-6 weeks of age, double knockout mice show more severe glucose intolerance than Tle3 single knockout mice
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endocrine/exocrine glands
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• 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
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• 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
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• 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
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• 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
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• pancreatic islets exhibit disorganized morphology at 4 weeks of age
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• 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
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• 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
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cellular
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• 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
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• 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
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growth/size/body
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• double knockout neonates exhibit normal body weight at P2; those surviving to weaning show normal body weight at 4-6 weeks of age
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