Examining the roles of MafB in the pancreatic islet

Abstract

Analysis of MafB-/- mice suggested that this transcription factor was essential to islet α- and β-cell formation during development, although the postnatal physiological impact could not be studied because these mutants died due to problems in neural development. Pancreas-wide mutant mice were generated by crossing MafBfl/fl mice with transgenic Pancreatic and duodenal homeobox 1 (Pdx1) driven-Cre mice to compare the postnatal significance of MafB (MafBΔpanc) and MafA/B (MafABΔpanc) to deficiencies associated with the related, β-cell-enriched MafA mutant (MafAΔpanc). Insulin+ cell production and β-cell activity was merely delayed in MafBΔpanc islets until MafA was comprehensively expressed, although MafABΔpanc mice died soon after birth from hyperglycemia. However, glucose-induced glucagon secretion was compromised in adult MafBΔpanc islet α-cells. Based upon these results, we conclude that MafB alone is important to islet α-cell activity, and not β-cell function in rodents. Interestingly, a notable difference between mice and humans is that MAFB is coexpressed with MAFA in adult human islet β-cells. In fact, we found that non-human primate (NHP) islet α- and β-cells also produce MAFB, implying that MAFB represents a unique functional signature of the primate islet β-cell. Stimulated insulin secretion experiments in the human β-cell line, EndoC-βH1, suggest that MAFB impacts cAMP-induced insulin secretion in the primate β-cell. Interestingly, MafB expression is silenced soon after birth in the rodent β-cell, only to be induced in a subset of maternal β-cells during pregnancy. Notably, the metabolic demands of pregnancy involve increases in β-cell mass and function. Our analysis of β-cell-specific MafB mutant (MafBΔβ) mice, generated by crossing MafBfl/fl mice with Rat Insulin Promoter (RIP)-Cre transgenic mice, suggests a specific role for MafB in β-cell proliferation during pregnancy. This thesis work sheds new light on the role of MafB in β-cells during pregnancy and its novel importance in primates.