Impaired MafB Activity Results in the Reduction in Pancreatic Alpha-and Beta-Cells.

During pancreatic development insulin+ cells transition from a MafA- to MafA+ state. Our previous results suggested that the expression of transcription factor MafB in insulin+ cells precedes this maturation step. To directly examine the role of MafB in this process, we analyzed embryonic pancreas from mice carrying a kreisler mutation in the mafBkr/kr gene. We show that this kr allele, for which serine is replaced by asparagine in the conserved, DNA-binding domain found in all bZIP family members, reduced the ability of MafB to activate both insulin and glucagon gene expression and that mice with this mutation had a significant reduction in the insulin and glucagon expressing cells. Mutation also resulted in the reduction of PDX-1+ and MafA+ cells with only a minor reduction in MafB+ cells. Interestingly, the proportion of MafB+ or PDX-1+ cells that also expressed insulin was reduced. However mutation in MafB did not affect the expression of Nkx2.2, Nkx6.1, Ngn3 and Pax6 suggesting that MafB does not affect the endocrine specification but rather plays a role in the maturation of insulin+ cells. Examination of Pax6 sey/sey mutant mice demonstrated a reduction in the insulin, glucagon, MatB, PDX-1 and MafA expressing cells. Since Pax6 expression was not altered in kreisler mice, our results suggest a role of MafB in the reduction of insulin and glucagon expressing cells in sey/sey mice. Furthermore, as in kreisler mice, the proportion of MafB+ or PDX-1+ cells expressing insulin was reduced in sey/sey mice, suggesting roles for both Pax6 and MafB in regulating the efficiency of terminal differentiation/maturation of insulin+ cells. Interestingly, unlike MafB and PDX-1 that were also expressed in some insulin- cells, all MafA+ cells in these mutant mice expressed insulin. Thus, our results indicate that MafA is a marker of terminally differentiated β-cell, and that Pax6 acts upstream of MafB, which in turn contributes to the expression of PDX-1 and MafA in differentiating insulin+ cells. [ABSTRACT FROM AUTHOR]