The MafB transcription factor is expressed in pancreatic α and β cells during development but becomes exclusive to α cells in adult rodents. Mafb -null ( Mafb −/− ) mice were reported to have reduced α- and β-cell numbers throughout embryonic development. To further analyze the postnatal function of MafB in the pancreas, we generated endocrine cell-specific ( Mafb Δ Endo ) and tamoxifen-dependent ( Mafb Δ TAM ) Mafb knockout mice. Mafb Δ Endo mice exhibited reduced populations of

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... e (insulin + ) and glucagon + cells at postnatal day 0, but the insulin + cell population recovered by 8 weeks of age. In contrast, the Arx + glucagon + cell fraction and glucagon expression remained decreased even in adulthood. Mafb Δ TAM mice, with Mafb deleted after pancreas maturation, also demonstrated diminished glucagon + cells and glucagon content without affecting β cells. A decreased Arx + glucagon + cell population in Mafb Δ Endo mice was compensated for by an increased Arx + pancreatic polypeptide + cell population. Furthermore, gene expression analyses from both Mafb Δ Endo and Mafb Δ TAM islets revealed that MafB is a key regulator of glucagon expression in α cells. Finally, both mutants failed to respond to arginine, likely due to impaired arginine transporter gene expression and glucagon production ability. Taken together, our findings reveal that MafB is critical for the functional maintenance of mouse α cells in vivo , including glucagon production and secretion, as well as in development.