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Insm1 cooperates with Neurod1 and Foxa2 to maintain mature pancreatic β-cell function.

Jia S, Ivanov A, Blasevic D, Müller T, Purfürst B, Sun W, Chen W, Poy MN, Rajewsky N, Birchmeier C - EMBO J. (2015)

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.

View Article: PubMed Central - PubMed

Affiliation: Developmental Biology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany cbirch@mdc-berlin.de jshiqi@mdc-berlin.de.

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Altered islet morphology in coInsm1 mutant miceA, B Comparison of β-cell number (A) and β-cell mass (B) in control and coInsm1 mice (n = 3 mice, 6–8 slides/animal). The number given in (A) refers to cell numbers/pancreas area.C, D Total pancreatic level of insulin (n = 6–12) (C) and Ins1 and Ins2 mRNA in control and coInsm1 mice (n = 5) (D).E Epithelial morphology and quantification of the packing density of islet cells in control and coInsm1 mice. The number given refers to cell numbers/islet area.F Analysis of cell death in β-cells of control and coInsm1 mice by TUNEL staining.G Comparison of proliferation in islets of control and coInsm1 mice using BrdU incorporation.H Distribution and quantification of glucagon+ cells in pancreata of control and coInsm1 mice.Data information: Data are presented as means ± SD; statistical significance was assessed by ANOVA and 2-tailed unpaired Student's t-test. *P < 0.05; **P < 0.01. (A, B, E–H) n = 3. Scale bars: 20 μm (E); 10 μm (F); 50 μm (G, H).
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fig03: Altered islet morphology in coInsm1 mutant miceA, B Comparison of β-cell number (A) and β-cell mass (B) in control and coInsm1 mice (n = 3 mice, 6–8 slides/animal). The number given in (A) refers to cell numbers/pancreas area.C, D Total pancreatic level of insulin (n = 6–12) (C) and Ins1 and Ins2 mRNA in control and coInsm1 mice (n = 5) (D).E Epithelial morphology and quantification of the packing density of islet cells in control and coInsm1 mice. The number given refers to cell numbers/islet area.F Analysis of cell death in β-cells of control and coInsm1 mice by TUNEL staining.G Comparison of proliferation in islets of control and coInsm1 mice using BrdU incorporation.H Distribution and quantification of glucagon+ cells in pancreata of control and coInsm1 mice.Data information: Data are presented as means ± SD; statistical significance was assessed by ANOVA and 2-tailed unpaired Student's t-test. *P < 0.05; **P < 0.01. (A, B, E–H) n = 3. Scale bars: 20 μm (E); 10 μm (F); 50 μm (G, H).

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.


Insm1 cooperates with Neurod1 and Foxa2 to maintain mature pancreatic β-cell function.

Jia S, Ivanov A, Blasevic D, Müller T, Purfürst B, Sun W, Chen W, Poy MN, Rajewsky N, Birchmeier C - EMBO J. (2015)

Altered islet morphology in coInsm1 mutant miceA, B Comparison of β-cell number (A) and β-cell mass (B) in control and coInsm1 mice (n = 3 mice, 6–8 slides/animal). The number given in (A) refers to cell numbers/pancreas area.C, D Total pancreatic level of insulin (n = 6–12) (C) and Ins1 and Ins2 mRNA in control and coInsm1 mice (n = 5) (D).E Epithelial morphology and quantification of the packing density of islet cells in control and coInsm1 mice. The number given refers to cell numbers/islet area.F Analysis of cell death in β-cells of control and coInsm1 mice by TUNEL staining.G Comparison of proliferation in islets of control and coInsm1 mice using BrdU incorporation.H Distribution and quantification of glucagon+ cells in pancreata of control and coInsm1 mice.Data information: Data are presented as means ± SD; statistical significance was assessed by ANOVA and 2-tailed unpaired Student's t-test. *P < 0.05; **P < 0.01. (A, B, E–H) n = 3. Scale bars: 20 μm (E); 10 μm (F); 50 μm (G, H).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492000&req=5

fig03: Altered islet morphology in coInsm1 mutant miceA, B Comparison of β-cell number (A) and β-cell mass (B) in control and coInsm1 mice (n = 3 mice, 6–8 slides/animal). The number given in (A) refers to cell numbers/pancreas area.C, D Total pancreatic level of insulin (n = 6–12) (C) and Ins1 and Ins2 mRNA in control and coInsm1 mice (n = 5) (D).E Epithelial morphology and quantification of the packing density of islet cells in control and coInsm1 mice. The number given refers to cell numbers/islet area.F Analysis of cell death in β-cells of control and coInsm1 mice by TUNEL staining.G Comparison of proliferation in islets of control and coInsm1 mice using BrdU incorporation.H Distribution and quantification of glucagon+ cells in pancreata of control and coInsm1 mice.Data information: Data are presented as means ± SD; statistical significance was assessed by ANOVA and 2-tailed unpaired Student's t-test. *P < 0.05; **P < 0.01. (A, B, E–H) n = 3. Scale bars: 20 μm (E); 10 μm (F); 50 μm (G, H).
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.

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.

View Article: PubMed Central - PubMed

Affiliation: Developmental Biology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany cbirch@mdc-berlin.de jshiqi@mdc-berlin.de.

Show MeSH
Related in: MedlinePlus