title: Microphthalmia transcription factor regulates pancreatic β-cell function.
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.
authors.affiliation: Stem Cell Center, Lund University, Sweden.
authors.forename: Magdalena A
authors.initials: MA
authors.lastname: Mazur
authors.forename: Marcus
authors.initials: M
authors.lastname: Winkler
authors.forename: Elvira
authors.initials: E
authors.lastname: Ganic
authors.forename: Jesper K
authors.initials: JK
authors.lastname: Colberg
authors.forename: Jenny K
authors.initials: JK
authors.lastname: Johansson
authors.forename: Hedvig
authors.initials: H
authors.lastname: Bennet
authors.forename: Malin
authors.initials: M
authors.lastname: Fex
authors.forename: Ulrike A
authors.initials: UA
authors.lastname: Nuber
authors.forename: Isabella
authors.initials: I
authors.lastname: Artner
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D001786:Blood Glucose; D005136:Eye Proteins; D018398:Homeodomain Proteins; D007328:Insulin; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; C110218:Pax4 protein, mouse; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins