MafB is required for islet β cell maturation

Abstract

Pancreatic endocrine cell differentiation depends on transcription factors that also contribute in adult insulin and glucagon gene expression. Islet cell development was examined in mice lacking MafB, a transcription factor expressed in immature ␣ (glucagon ؉ ) and ␤ (insulin ؉ ) cells and capable of activating insulin and glucagon expression in vitro. We observed that MafB ؊/؊ embryos had reduced numbers of insulin ؉ and glucagon ؉ cells throughout development, whereas the total number of endocrine cells was unchanged. Moreover, production of insulin ؉ cells was delayed until embryonic day (E) 13.5 in mutant mice and coincided with the onset of MafA expression, a MafB-related activator of insulin transcription. MafA expression was only detected in the insulin ؉ cell population in MafB mutants, whereas many important regulatory proteins continued to be expressed in insulin ؊ ␤ cells. However, Pdx1, Nkx6.1, and GLUT2 were selectively lost in these insulin-deficient cells between E15.5 and E18.5. MafB appears to directly regulate transcription of these genes, because binding was observed within endogenous control region sequences. These results demonstrate that MafB plays a previously uncharacterized role by regulating transcription of key factors during development that are required for the production of mature ␣ and ␤ cells.insulin ͉ MafA ͉ pancreas development

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

“…3b) Neurog3, tended to be increased in activin A-treated MIN6 cells (Fig. 3b) [28]. These results are similar to our previous data comparing sorted immature and mature beta cells, for instance, with opposite changes in expression of Mafa and Mafb [1].…”

“…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]. Activin A did not increase Mafb expression in primary mouse islet cells, as it did in MIN6, probably because islet alpha cells express high levels of Mafb [41] and a small increase in beta cell Mafb expression with activin A treatment might not have been detectable above control.…”

Pancreas organogenesis: From bud to plexus to gland

“…The bZIP factors MafA/B are expressed relatively later in development and are essential to acquire and maintain the mature state of hormone-expressing cells by activating genes important for b-cell function. These genes include insulin, Pdx1, GLUT2, Nkx6.1, Slc30a8 (zinc transporter) and G6pc2 (Glucose-6-phosphatase catalytic sub-unit 2 protein) (Aramata et al, 2005;Zhao et al, 2005, Raum et al, 2006Artner et al, 2007). During development, b-cells move from a MafB þ immature state to MafA þ / MafB þ , and finally, to a MafA þ mature state.…”

Transcription factor regulation of pancreatic organogenesis, differentiation and maturation

“…209 MafB mutant mice have reduced a-and b-cells although the endocrine cell number is unaltered and these mice die shortly after birth (Table 1). 210 Further, a comparison between wild type and MafB mutant mice revealed no difference in the endocrine cell numbers. 210 MafA ¡/¡ mice are viable but undergo b-cell dysfunction ultimately leading to glucose intolerance and diabetes.…”