MafA and MafB Regulate Pdx1 Transcription through the Area II Control Region in Pancreatic β Cells

Abstract

Pancreatic-duodenal homeobox factor-1 (Pdx1) is highly enriched in islet β cells and integral to proper cell development and adult function. Of the four conserved 5′-flanking sequence blocks that contribute to transcription in vivo, Area II (mouse base pairs -2153/-1923) represents the only mammalian specific control domain. Here we demonstrate that regulation of β-cell-enriched Pdx1 expression by the MafA and MafB transcription factors is exclusively through Area II. Thus, these factors were found to specifically activate through Area II in cell line transfection-based assays, and MafA, which is uniquely expressed in adult islet β cells was only bound to this region in quantitative chromatin immunoprecipitation studies. MafA and MafB are produced in β cells during development and were both bound to Area II at embryonic day 18.5. Expression of a transgene driven by Pdx1 Areas I and II was also severely compromised during insulin+ cell formation in MafB-/- mice, consistent with the importance of this large Maf in β-cell production and Pdx1 expression. These findings illustrate the significance of large Maf proteins to Pdx1 expression in β cells, and in particular MafB during pancreatic development.