Microphthalmia transcription factor regulates pancreatic β-cell function

Research output: Contribution to journalArticle

Abstract

Precise regulation of β-cell function is crucial for maintaining blood glucose homeostasis. Pax6 is an essential regulator of β-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 β-cell mass in adult mice. Mutant β-cells secrete more insulin in response to glucose than wild-type cells, suggesting that Mitf is involved in regulating β-cell function. In fact, the transcription of genes critical for maintaining glucose homeostasis (insulin and Glut2) and β-cell formation and function (Pax4 and Pax6) is significantly upregulated in Mitf mutant islets. The increased Pax6 expression may cause the improved β-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 β-cells. We demonstrate that Mitf directly regulates Pax6 transcription and controls β-cell function.

Details

Authors
  • Magdalena Mazur
  • Marcus Winkler
  • Elvira Ganic
  • Jesper K. Colberg
  • Jenny Johansson
  • Hedvig Bennet
  • Malin Fex
  • Ulrike Nuber
  • Isabella Artner
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes

Keywords

  • MELANOMA, GENE, DIFFERENTIATION, MELANOCYTES, PAX6, GLUCOSE, MITF, EARLY-ONSET, NEURAL CREST, DIABETES-MELLITUS
Original languageEnglish
Pages (from-to)2834-2842
JournalDiabetes
Volume62
Issue number8
Publication statusPublished - 2013
Publication categoryResearch
Peer-reviewedYes

Related research output

Ganic, E., 2015, Stem Cell Center, Lund University. 134 p.

Research output: ThesisDoctoral Thesis (compilation)

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