Insm1 cooperates with Neurod1 and Foxa2 to maintain mature pancreatic β-cell function.
Bottom Line: We defined Insm1, Neurod1 and Foxa2 binding sites associated with genes deregulated in Insm1 mutant β-cells.Human genomic sequences corresponding to the murine sites occupied by Insm1/Neurod1/Foxa2 were enriched in single nucleotide polymorphisms associated with glycolytic traits.Thus, our data explain part of the mechanisms by which β-cells maintain maturity: Combinatorial Insm1/Neurod1/Foxa2 binding identifies regulatory sequences that maintain the mature gene expression program in β-cells, and disruption of this network results in functional failure.
Affiliation: Developmental Biology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany email@example.com firstname.lastname@example.org.Show MeSH
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Mentions: We next tested whether decreased insulin release was caused by β-cell loss or reduced insulin production. Pancreatic β-cell numbers were comparable in control and mutant mice (Fig 3A), but β-cell mass was mildly reduced in the mutants (Fig 3B). Insulin content and insulin-1 (Ins1) but not insulin-2 (Ins2) mRNAs were mildly reduced in coInsm1 mutant pancreata (Fig 3C and D). Mice that lack the insulin-1 gene remain glucose tolerant (Leroux et al, 2001), indicating that the mild downregulation of insulin-1 mRNA cannot account for the pronounced deficit in insulin secretion observed in coInsm1 mutant mice.
Affiliation: Developmental Biology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany email@example.com firstname.lastname@example.org.