MafA and MafB activity in pancreatic β cells

Abstract

Analyses in mouse models have revealed crucial roles for MafA (musculoaponeurotic fibrosarcoma oncogene family A) and MafB in islet β cells, with MafB being required during development and MafA in adults. These two closely related transcription factors regulate many genes essential for glucose sensing and insulin secretion in a cooperative and sequential manner. Significantly, the switch from MafB to MafA expression also appears to be vital for functional maturation of β cells produced by human embryonic stem (hES) cell differentiation. This review summarizes the discovery, distribution, and function of MafA and MafB in rodent pancreatic β cells, and describes some key questions regarding their importance to β cells.

Figure 1. Roles of MafA and MafB in mouse β cells

MafA and MafB are expressed in a dynamic temporal pattern (top panel)^, and required at distinct stages in mouse β cells (bottom panels). MafB is critical to β cell terminal differentiation through regulation of key β genes (blue). Thus MafB binds and directly initiates the insulin and MafA transcription in developing β cells. In addition, it is required at E18.5 for expression of β cell factors involved in glucose-stimulated insulin secretion (e.g. pdx1, slc2a2, and slc30a8). MafA regulates most of these β cell genes (red) in adult when MafB in silenced.

Figure 2. A cascade of transcription factors plays important roles in pancreas development

The schematic diagram is a simplified model indicating transcription factors expressed at each stage of rodent pancreas development. The large Maf transcription factors MafB and MafA are located at the bottom of the cascade. MafB is required for the terminal differentiation of α and β cells while MafA is critical for β cell function in adult.

Figure 3. Summary of the differences between MafA and MafB in phosphatase-sensitive DNA binding and endogenous hormone gene activation assays

The indicated MafB/A chimeras have been tested for phosphatase-sensitive DNA binding in gel shift assays, and for their ability to activate endogenous insulin and glucagon gene expression in both the chicken in ovo electroporation and cell line based assays. “?”, to be determined.