MafA and MafB Regulate Genes Critical to β-Cells in a Unique Temporal Manner

Abstract

OBJECTIVESeveral transcription factors are essential to pancreatic islet β-cell development, proliferation, and activity, including MafA and MafB. However, MafA and MafB are distinct from others in regard to temporal and islet cell expression pattern, with β-cells affected by MafB only during development and exclusively by MafA in the adult. Our aim was to define the functional relationship between these closely related activators to the β-cell.RESEARCH DESIGN AND METHODSThe distribution of MafA and MafB in the β-cell population was determined immunohistochemically at various developmental and perinatal stages in mice. To identify genes regulated by MafB, microarray profiling was performed on wild-type and MafB−/− pancreata at embryonic day 18.5, with candidates evaluated by quantitative RT-PCR and in situ hybridization. The potential role of MafA in the expression of verified targets was next analyzed in adult islets of a pancreas-wide MafA mutant (termed MafAΔPanc).RESULTSMafB was produced in a larger fraction of β-cells than MafA during development and found to regulate potential effectors of glucose sensing, hormone processing, vesicle formation, and insulin secretion. Notably, expression from many of these genes was compromised in MafAΔPanc islets, suggesting that MafA is required to sustain expression in adults.CONCLUSIONSOur results provide insight into the sequential manner by which MafA and MafB regulate islet β-cell formation and maturation.

Growth arrest specific protein (GAS) 6: a role in the regulation of proliferation and functional capacity of the perinatal rat beta cell

“…In the perinatal period, a transition from Mafb to Mafa accompanies differentiation of beta cells in a temporal way, where Mafb expression is gradually reduced as Mafa expression increases so that mature beta cells only express Mafa [10,16]. Interestingly, a recent study showed that Mafb was re-expressed in proliferative beta cells [31].…”

“…Diet-induced changes in the temporal expression of transcription factors important for beta cell differentiation and maturation, such as v-maf musculoaponeurotic fibrosarcoma oncogene (MAF) homologue A and B and pancreatic duodenal homeobox-1 (PDX1), very likely play a role in development of the phenotype of LP offspring [14][15][16]. The regulation of these factors is, however, not fully clarified.…”

Pancreas organogenesis: From bud to plexus to gland

“…Thus, MafB is essentially absent from mature adult b-cells and its expression is restricted to a-cells in the adult pancreas. The switch from MafB þ to MafA þ in b-cells occurs during a period of b-cell maturation and this process is associated with up-regulation of Pdx1 expression (Nishimura et al 2006;Artner et al, 2010). MafA mutants have no effect on endocrine cell development but the mice become glucose-intolerant postnatally .…”

“…Whereas MafA function is b-cell specific, MafB is required for both a-cell and b-cell differentiation/ maturation, and is a more potent regulator of embryonic b-cell development than MafA. MafB À/À mice have reduced a and b-cell numbers, as well as some form of apparently delayed bcell development (Artner et al, , 2010.…”

Virgin Beta Cells Persist throughout Life at a Neogenic Niche within Pancreatic Islets

“…Ucn3 is a late maturation marker for primary and stem cell-derived beta cells (Blum et al, 2012;van der Meulen et al, 2012) that continued to increase progressively weeks after beta cell expression of Nkx6-1 and Mafa reached steady state, and coincided with the gradual loss of Mafb from beta cells ( Figure 1A) (Artner et al, 2010).…”