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The serine\/threonine kinase mTOR integrates various environmental cues to serve as a central regulator of cell growth, metabolism, and function. We report here that tuberous sclerosis complex 1 (TSC1), a negative regulator of mTOR activity, establishes a stage\u2010dependent program for Schwann cell lineage progression and myelination by controlling cell proliferation and myelin homeostasis. <jats:italic>Tsc1<\/jats:italic> ablation in Schwann cell progenitors in mice resulted in activation of mTOR signaling, and caused over\u2010proliferation of Schwann cells and blocked their differentiation, leading to hypomyelination. Transcriptome profiling analysis revealed that mTOR activation in <jats:italic>Tsc1<\/jats:italic> mutants resulted in upregulation of a polo\u2010like kinase (PLK)\u2010dependent pathway and cell cycle regulators. Attenuation of mTOR or pharmacological inhibition of polo\u2010like kinases partially rescued hypomyelination caused by <jats:italic>Tsc1<\/jats:italic> loss in the developing peripheral nerves. In contrast, deletion of <jats:italic>Tsc1<\/jats:italic> in mature Schwann cells led to redundant and overgrown myelin sheaths in adult mice. Together, our findings indicate stage\u2010specific functions for the TSC1\u2010mTOR\u2010PLK signaling axis in controlling the transition from proliferation to differentiation and myelin homeostasis during Schwann cell development.<\/jats:p>","DOI":"10.1002\/glia.23449","type":"journal-article","created":{"date-parts":[[2018,5,3]],"date-time":"2018-05-03T19:52:03Z","timestamp":1525377123000},"page":"1947-1959","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["<scp>T<\/scp>he <scp>TSC<\/scp>1\u2010m<scp>TOR\u2010PLK<\/scp> axis regulates the homeostatic switch from <scp>S<\/scp>chwann cell proliferation to myelination in a stage\u2010specific manner"],"prefix":"10.1002","volume":"66","author":[{"given":"Minqing","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Division of Experimental Hematology and Cancer Biology Cincinnati Children's Hospital Medical Center, University of Cincinnati Cincinnati Ohio"},{"name":"The Institute of Cognitive Neuroscience, East China Normal University Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rohit","family":"Rao","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Experimental Hematology and Cancer Biology Cincinnati Children's Hospital Medical Center, University of Cincinnati Cincinnati Ohio"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jincheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Experimental Hematology and Cancer Biology Cincinnati Children's Hospital Medical Center, University of Cincinnati Cincinnati Ohio"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiajia","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Experimental Hematology and Cancer Biology Cincinnati Children's Hospital Medical Center, University of Cincinnati Cincinnati Ohio"},{"name":"Key Laboratory of Birth Defects Children's Hospital of Fudan University Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lingli","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Experimental Hematology and Cancer Biology Cincinnati Children's Hospital Medical Center, University of Cincinnati Cincinnati Ohio"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lai Man","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Experimental Hematology and Cancer Biology Cincinnati Children's Hospital Medical Center, University of Cincinnati Cincinnati Ohio"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonah R.","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Neurology and Programs in Biomedical and Neurosciences University of California San Francisco California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huimin","family":"Wang","sequence":"additional","affiliation":[{"name":"The Institute of Cognitive Neuroscience, East China Normal University Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6846-9014","authenticated-orcid":false,"given":"Q. 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