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This Article Accepted manuscript (PDF) Supplementary figures All Versions of this Article: JOE-08-0063v1 198/2/271    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Artner, I. Articles by Stein, R. Search for Related Content PubMed PubMed Citation Articles by Artner, I. Articles by Stein, R.

I Artner, Stem Cell Center, Lund University, Lund, 22184, Sweden
Y Hang, Nashville, United States
M Guo, Molecular Physiology and Physiology, Vanderbilt University Medical Center, Nashville, United States
G Gu, Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, United States
R Stein, Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, United States

Correspondence: Isabella Artner, Email: isabella.artner{at}med.lu.se

Abstract

As successful generation of insulin producing cells could be used for diabetes treatment, a concerted effort is being made to understand the molecular programs underlying islet beta cell formation and function. The closely related MafA and MafB transcription factors are both key mammalian beta cell regulators. MafA and MafB are co-expressed in insulin+ beta cells during embryogenesis, while in the adult pancreas MafA is only produced in beta cells and MafB in glucagon+ alpha cells. MafB-/- animals are also deficient in insulin+ and glucagon+ cell production during embryogenesis. However, only MafA over-expression selectively induced endogenous Insulin mRNA production in cell line based assays, while MafB specifically promoted Glucagon expression. Here we analyzed if these factors were sufficient to induce insulin+ and/or glucagon+ cell formation within embryonic endoderm using the chick in ovo electroporation assay. Ectopic expression of MafA, but not MafB, promoted Insulin production, however neither MafA nor MafB were capable of inducing Glucagon. Co-electroporation of MafA with the Ngn3 transcription factor resulted in the development of more organized cell clusters containing both insulin and glucagon producing cells. Analysis of chimeric proteins of MafA and MafB demonstrated that chick Insulin activation depended on sequences within the MafA C-terminal DNA binding domain. MafA was also bound to Insulin and Glucagon transcriptional control sequences in mouse embryonic pancreas and beta cell lines. Collectively, these results demonstrate a unique ability for MafA to independently activate Insulin transcription.