Dual effect of raptor on neonatal B-cell proliferation and identity maintenance

Immature pancreatic b-cells are highly proliferative, and the expansion of b-cells during the early neonatal period largely determines functional b-cell mass; however, the mechanisms are poorly characterized. We generated Ngn3RapKO mice (ablation of Raptor, an essential component of mechanistic target of rapamycin [mTORC1] in Ngn3⁺ endocrine progenitor cells) and found that mTORC1 was dispensable for endocrine cell lineage formation but specifically regulated both proliferation and identity maintenance of neonatal b-cells. Ablation of Raptor in neonatal b-cells led to autonomous loss of cell identity, decelerated cell cycle progression, compromised proliferation, and caused neonatal diabetes as a result of inadequate establishment of functional b-cell mass at postnatal day 14. Completely different from mature b-cells, Raptor regulated G1/S and G2/M phase cell cycle transition, thus permitting a high proliferation rate in neonatal b-cells. Moreover, Ezh2 was identified as a critical downstream target of mTORC1 in neonatal b-cells, which was responsible for G2/M phase transition and proliferation. Our discovery of the dual effect of mTORC1 in immature b-cells has revealed a potential target for replenishing functional b-cell pools by promoting both expansion and functional maturation of newly formed immature b-cells.