title: VHL-mediated disruption of Sox9 activity compromises β-cell identity and results in diabetes mellitus.
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.
authors.affiliation: Diabetes Center, Department of Medicine, University of California at San Francisco, San Francisco, California 94143, USA;
authors.forename: Sapna
authors.initials: S
authors.lastname: Puri
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Akiyama
authors.forename: Matthias
authors.initials: M
authors.lastname: Hebrok
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D002460:Cell Line; D003920:Diabetes Mellitus / Q000235:genetics* / Q000503:physiopathology*; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism; D008297:Male; D051379:Mice; D055758:SOX9 Transcription Factor / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D055758:SOX9 Transcription Factor; D051794:Von Hippel-Lindau Tumor Suppressor Protein
keywords: dedifferentiation; diabetes mellitus; hypoxia; von-Hippel Lindau; β cell