E-CBIL-39 - Transcription profiling of wild type and Foxa2 knock out mouse mature beta cells
Submitted on 20 September 2007, released on 22 September 2007, last updated on 1 May 2014
The winged helix transcription factor Foxa2 regulates Pdx1 gene expression and fetal endocrine pancreas development. We show here by inducible gene ablation that Foxa2 inactivation in mature beta-cells induces hyperinsulinemic hypoglycemia in Foxa2loxP/loxP, Pdx1-CreERT2 adult mice. Mutant beta-cells exhibited a markedly increased pool of docked insulin granules, some of which were engaged in sequential or compound exocytosis, consistent with an increased first phase glucose-stimulated insulin secretion. Expression of multiple genes involved in vesicular trafficking, membrane targeting and fuel-secretion pathways is dependent on Foxa2. In addition, impaired cytosolic Ca2+ oscillations and elevated intracellular cAMP production accompanied this secretory defect, and were likely contributors to the sensitization of the exocytotic machinery. Thus, in the absence of Foxa2, alterations in intracellular second messenger signaling redistribute the insulin granules into the readily releasable pool. We conclude that Foxa2 is required both for the fetal pancreas development and for the function of mature beta-cells.
transcription profiling by array, genetic modification
Foxa2 controls vesicle docking and insulin secretion in mature beta-cells. Nan Gao, Peter White, Nicolai Doliba, Maria L. Golson, Franz M. Matschinsky, and Klaus H. Kaestner. Cell Metab 6(4):267-79 (2007), PMID:17908556