The MafA Transcription Factor Becomes Essential to Islet β-Cells Soon After Birth

  1. Roland Stein1
  1. 1Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN
  2. 2Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN
  3. 3Department of Biomedical Informatics, Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, TN
  4. 4Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN
  5. 5Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN
  1. Corresponding author: Roland Stein, roland.stein{at}vanderbilt.edu.

Abstract

The large Maf transcription factors, MafA and MafB, are expressed with distinct spatial–temporal patterns in rodent islet cells. Analysis of Mafa−/− and pancreas-specific Mafa∆panc deletion mutant mice demonstrated a primary role for MafA in adult β-cell activity, different from the embryonic importance of MafB. Our interests here were to precisely define when MafA became functionally significant to β-cells, to determine how this was affected by the brief period of postnatal MafB production, and to identify genes regulated by MafA during this period. We found that islet cell organization, β-cell mass, and β-cell function were influenced by 3 weeks of age in MafaΔpanc mice and compromised earlier in MafaΔpanc;Mafb+/− mice. A combination of genome-wide microarray profiling, electron microscopy, and metabolic assays were used to reveal mechanisms of MafA control. For example, β-cell replication was produced by actions on cyclin D2 regulation, while effects on granule docking affected first-phase insulin secretion. Moreover, notable differences in the genes regulated by embryonic MafB and postnatal MafA gene expression were found. These results not only clearly define why MafA is an essential transcriptional regulator of islet β-cells, but also why cell maturation involves coordinated actions with MafB.

Footnotes

  • Received June 26, 2013.
  • Accepted February 3, 2014.

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  1. Diabetes vol. 63 no. 6 1994-2005
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