MafA is required for postnatal proliferation of pancreatic β-cells

PLoS One. 2014 Aug 15;9(8):e104184. doi: 10.1371/journal.pone.0104184. eCollection 2014.

Abstract

The postnatal proliferation and maturation of insulin-secreting pancreatic β-cells are critical for glucose metabolism and disease development in adults. Elucidation of the molecular mechanisms underlying these events will be beneficial to direct the differentiation of stem cells into functional β-cells. Maturation of β-cells is accompanied by increased expression of MafA, an insulin gene transcription factor. Transcriptome analysis of MafA knockout islets revealed MafA is required for the expression of several molecules critical for β-cell function, including Glut2, ZnT8, Granuphilin, Vdr, Pcsk1 and Urocortin 3, as well as Prolactin receptor (Prlr) and its downstream target Cyclin D2 (Ccnd2). Inhibition of MafA expression in mouse islets or β-cell lines resulted in reduced expression of Prlr and Ccnd2, and MafA transactivated the Prlr promoter. Stimulation of β-cells by prolactin resulted in the phosphorylation and translocation of Stat5B and an increased nuclear pool of Ccnd2 via Prlr and Jak2. Consistent with these results, the loss of MafA resulted in impaired proliferation of β-cells at 4 weeks of age. These results suggest that MafA regulates the postnatal proliferation of β-cells via prolactin signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Cell Line
  • Cell Proliferation
  • Cyclin D2 / genetics
  • Cyclin D2 / metabolism
  • Gene Expression
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Genes, Reporter
  • Humans
  • Insulin-Secreting Cells / metabolism*
  • Islets of Langerhans / metabolism
  • Maf Transcription Factors, Large / genetics*
  • Maf Transcription Factors, Large / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Promoter Regions, Genetic
  • Rats
  • Receptors, Prolactin / genetics
  • Signal Transduction
  • Transcriptome

Substances

  • Cyclin D2
  • Maf Transcription Factors, Large
  • Mafa protein, mouse
  • Receptors, Prolactin

Grant support

This study was supported by JSPS KAKENHI (22591022), a grant from the National Center for Global Health and Medicine (22–103), the Takeda Science Foundation, and the Japan Diabetes Foundation to WN, JSPS KAKENHI (21390283) and a grant from the National Center for Global Health and Medicine (25–102) to KY. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.