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

Abstract

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.

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].…”

“…Adult rat islets are less responsive to mitogenic stimuli than neonatal rat islets. This is partly due to high production levels of factors associated with beta cell differentiation and inhibition of proliferation such as MAFA and P27 [8,10]. Thus, the lack of GAS6 effects in adult rat beta cells could be due to the abundance of such factors.…”

“…The expansion arises from the proliferation of existing beta cells and by neogenesis from progenitor cells and declines after birth [9,10].…”

Reciprocal modulation of adult beta cell maturity by activin A and follistatin

“…This pattern of Mafa and Mafb expression in activin A-treated cells is consistent with a dedifferentiated, immature beta cell phenotype, as it occurs during endocrine development. In murine pancreas development, Mafb is expressed before Mafa, followed by Mafb downregulation in adult beta cells [40]. Mafb is required for beta cell maturation and directly regulates expression of Mafa, Pdx1, Nkx6-1, Glut2 and insulin [28].…”

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 .…”