A switch from MafB to MafA expression accompanies differentiation to pancreatic β-cells

• DOI: 10.1016/j.ydbio.2006.02.028
• Publication Date: 2006-04-05T14:44:34Z
• Authors: Wataru Nishimura; Takuma Kondo; Therese Salameh; Ilham El Khattabi; Rikke Dodge; Susan Bonner-Weir; Arun Sharma
• Keywords: Maf Transcription Factors, Large; Maf factors; Pancreatic islets; MafB Transcription Factor; Pancreatic development; Transfection; Models, Biological; Islets of Langerhans; Mice; 03 medical and health sciences; Genes, Reporter; Pregnancy; Animals; Humans; Insulin; RNA, Messenger; Molecular Biology; Cell Proliferation; 0303 health sciences; Base Sequence; Endocrine differentiation; Gene Expression Regulation, Developmental; Cell Differentiation; Cell Biology; Glucagon; MafA; MafB; Mice, Inbred C57BL; Female; Insulin gene transcription factor; Developmental Biology; HeLa Cells

Major insulin gene transcription factors, such as PDX-1 or NeuroD1, have equally important roles in pancreatic development and the differentiation of pancreatic endocrine cells. Previously, we identified and cloned another critical insulin gene transcription factor MafA (RIPE3b1) and reported that other Maf factors were expressed in pancreatic endocrine cells. Maf factors are important regulators of cellular differentiation; to understand their role in differentiation of pancreatic endocrine cells, we analyzed the expression pattern of large-Maf factors in the pancreas of embryonic and adult mice. Ectopically expressed large-Maf factors, MafA, MafB, or cMaf, induced expression from insulin and glucagon reporter constructs, demonstrating a redundancy in their function. Yet in adult pancreas, cMaf was expressed in both alpha- and beta-cells, and MafA and MafB showed selective expression in the beta- and alpha-cells, respectively. Interestingly, during embryonic development, a significant proportion of MafB-expressing cells also expressed insulin. In embryos, MafB is expressed before MafA, and our results suggest that the differentiation of beta-cells proceeds through a MafB+ MafA- Ins+ intermediate cell to MafB- MafA+ Ins+ cells. Furthermore, the MafB to MafA transition follows induction of PDX-1 expression (Pdx-1(high)) in MafB+ Ins+ cells. We suggest that MafB may have a dual role in regulating embryonic differentiation of both beta- and alpha-cells while MafA may regulate replication/survival and function of beta-cells after birth. Thus, this redundancy in the function and expression of the large-Maf factors may explain the normal islet morphology observed in the MafA knockout mice at birth.