Microphthalmia transcription factor regulates pancreatic β-cell function.

Precise regulation of beta-cell function is crucial for maintaining blood glucose homeostasis. Pax6 is an essential regulator of beta-cell-specific factors like insulin and Glut2. Studies in the developing eye suggest that Pax6 interacts with Mitf to regulate pigment cell differentiation. Here, we show that Mitf, like Pax6, is expressed in all pancreatic endocrine cells during mouse postnatal development and in the adult islet. A Mitf loss-of-function mutation results in improved glucose tolerance and enhanced insulin secretion but no increase in beta-cell mass in adult mice. Mutant beta-cells secrete more insulin in response to glucose than wild-type cells, suggesting that Mitf is involved in regulating beta-cell function. In fact, the transcription of genes critical for maintaining glucose homeostasis (insulin and Glut2) and beta-cell formation and function (Pax4 and Pax6) is significantly upregulated in Mitf mutant islets. The increased Pax6 expression may cause the improved beta-cell function observed in Mitf mutant animals, as it activates insulin and Glut2 transcription. Chromatin immunoprecipitation analysis shows that Mitf binds to Pax4 and Pax6 regulatory regions, suggesting that Mitf represses their transcription in wild-type beta-cells. We demonstrate that Mitf directly regulates Pax6 transcription and controls beta-cell function.