Dual Effect of Raptor on Neonatal β Cell Proliferation and Identity Maintenance
Dual Effect of Raptor on Neonatal β Cell Proliferation and Identity Maintenance
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Raptor 对新生儿β细胞增殖和身份维持的双重影响
作者：
Yanqiu Wang;Jiajun Sun;Qicheng Ni;Aifang Nie;Yanyun Gu;Shu Wang;Weizhen Zhang;Guang Ning;Weiqing Wang;Qidi Wang
未成熟的胰腺β细胞高度增殖，新生儿早期β细胞的扩增在很大程度上决定了功能性β细胞的数量；然而，其机制尚不清楚。我们建立了Ngn3RapKO小鼠(在Ngn3+内分泌祖细胞中消融Raptor，雷帕霉素机械性靶点的关键成分)，发现mTORc1对内分泌细胞系的形成是必不可少的，但特异性地调节新生β-细胞的增殖和身份维持。去除新生β细胞中的Raptor后，由于出生后14天功能β细胞团的建立不充分，导致细胞自主丧失特性，细胞周期进程减慢，增殖受阻，并导致新生儿糖尿病。与成熟的β细胞完全不同，Raptor调控G1/S和G2/M期细胞周期转换，从而使新生β细胞具有高增殖率。此外，在新生儿β细胞中，Ezh2被认为是mTORC1下游的关键靶点，负责G2/M期的转变和增殖。我们在未成熟β细胞中发现mTORC 1的双重作用，揭示了通过促进新形成的未成熟β细胞的扩张和功能成熟来补充功能β细胞库的潜在靶点。
Immature pancreatic β-cells are highly proliferative, and the expansion of β-cells during the early neonatal period largely determines functional β-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 β-cells. Ablation of Raptor in neonatal β-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 β-cell mass at postnatal day 14. Completely different from mature β-cells, Raptor regulated G1/S and G2/M phase cell cycle transition, thus permitting a high proliferation rate in neonatal β-cells. Moreover, Ezh2 was identified as a critical downstream target of mTORC1 in neonatal β-cells, which was responsible for G2/M phase transition and proliferation. Our discovery of the dual effect of mTORC1 in immature β-cells has revealed a potential target for replenishing functional β-cell pools by promoting both expansion and functional maturation of newly formed immature β-cells.