Rheb1 is required for mTORC1 and myelination in postnatal brain development

来源 :中国神经科学学会第九届全国学术会议暨第五届会员代表大会 | 被引量 : 0次 | 上传用户:jorry1983
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  mTor kinase is involved in cell growth, proliferation, and differentiation.The roles of mTor activators, Rheb1 and Rheb2, have not been established in vivo.We generated mice with conditional genetic deletions of Rheb1 and Rheb2.Germiline deletion of Rheb1 (Actin-cre) results in embryonic death between E10.5 and E11.5 while mutant mice with germiline deletion of Rheb2 mature to adulthood without obvious physical deficits.In cultured mouse embryonic fibroblasts (MEFs) from individual E10.5 embryos, insulin and amino acids activated mTORC1 signalings are selectively impaired in Rheb1-/-MEFs.To examine the roles of Rheb1 in vivo, we generated Rheb1 f/f, Nestincre mice in which Rheb1 was conditionally excised in neural progenitor cells.The mutants were born at expected Medelian ratios and survived up to 6 weeks after birth, mTORC1 signaling is abolished and mTORC2 signaling is increased in developing brain of Rheb1f/f, Nestin-cre.Remarkably, in Rheb1 f/f, Nestin-cre mutants, the gross morphology of the brains at early postnatal stages was preserved, whereas the myelin formation in later developmental stages was significantly impaired.Since TSC mutants in which mTORC 1 signaling were upregulated were previously reported with hypomyelination phenotype, we generated Rosa26 Rheb1 transgenic mouse which conditionally express Rheb 1 in neural progenitor cells to examine whether increasing Rheb1/mTORC 1 activity promotes myelination, or causes hypomyelination.Rheb1 transgene increases mTORC1 activity and promotes myelin formation in the brain, In addition, the Rheb1 transgene rescues mTORC 1 signaling and hypomyelination in the Rheblf/f, Nesin-cre mice.Our study demonstrates that Rheb1, but not Rheb2, is critical for embryonic survival and mTORC1 signaling.And Rheb1 is essential for myelin development in the brain, and suggests that mTORC1 signaling plays a role in selective cellular adaptations, rather than general cellular viability.
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