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Genes Dev. 2013 Dec 1;27(23):2563-75. doi: 10.1101/gad.227785.113.

VHL-mediated disruption of Sox9 activity compromises β-cell identity and results in diabetes mellitus.

Author information

  • 1Diabetes Center, Department of Medicine, University of California at San Francisco, San Francisco, California 94143, USA;

Abstract

Precise functioning of the pancreatic β cell is paramount to whole-body glucose homeostasis, and β-cell dysfunction contributes significantly to diabetes mellitus. Using transgenic mouse models, we demonstrate that deletion of the von Hippel-Lindau (Vhlh) gene (encoding an E3 ubiquitin ligase implicated in, among other functions, oxygen sensing in pancreatic β cells) is deleterious to canonical β-cell gene expression. This triggers erroneous expression of factors normally active in progenitor cells, including effectors of the Notch, Wnt, and Hedgehog signaling cascades. Significantly, an up-regulation of the transcription factor Sox9, normally excluded from functional β cells, occurs upon deletion of Vhlh. Sox9 plays important roles during pancreas development but does not have a described role in the adult β cell. β-Cell-specific ectopic expression of Sox9 results in diabetes mellitus from similar perturbations in β-cell identity. These findings reveal that assaults on the β cell that impact the differentiation state of the cell have clear implications toward our understanding of diabetes mellitus.

KEYWORDS:

dedifferentiation; diabetes mellitus; hypoxia; von-Hippel Lindau; β cell

PMID:
24298056
[PubMed - indexed for MEDLINE]
PMCID:
PMC3861670
Free PMC Article

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