title: mTOR signaling promotes stem cell activation via counterbalancing BMP-mediated suppression during hair regeneration.
abstract: Hair follicles (HFs) undergo cycles of degeneration (catagen), rest (telogen), and regeneration (anagen) phases. Anagen begins when the hair follicle stem cells (HFSCs) obtain sufficient activation cues to overcome suppressive signals, mainly the BMP pathway, from their niche cells. Here, we unveil that mTOR complex 1 (mTORC1) signaling is activated in HFSCs, which coincides with the HFSC activation at the telogen-to-anagen transition. By using both an inducible conditional gene targeting strategy and a pharmacological inhibition method to ablate or inhibit mTOR signaling in adult skin epithelium before anagen initiation, we demonstrate that HFs that cannot respond to mTOR signaling display significantly delayed HFSC activation and extended telogen. Unexpectedly, BMP signaling activity is dramatically prolonged in mTOR signaling-deficient HFs. Through both gain- and loss-of-function studies in vitro, we show that mTORC1 signaling negatively affects BMP signaling, which serves as a main mechanism whereby mTORC1 signaling facilitates HFSC activation. Indeed, in vivo suppression of BMP by its antagonist Noggin rescues the HFSC activation defect in mTORC1-null skin. Our findings reveal a critical role for mTOR signaling in regulating stem cell activation through counterbalancing BMP-mediated repression during hair regeneration.
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China University of Chinese Academy of Sciences, Beijing 100190, China.
authors.forename: Zhili
authors.initials: Z
authors.lastname: Deng
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Lei
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China University of Chinese Academy of Sciences, Beijing 100190, China.
authors.forename: Xudong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China University of Chinese Academy of Sciences, Beijing 100190, China.
authors.forename: Huishan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Huimin
authors.initials: H
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China University of Chinese Academy of Sciences, Beijing 100190, China.
authors.forename: Xinyue
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Ning
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Yujing
authors.initials: Y
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Tongbiao
authors.initials: T
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.
authors.forename: Jiaxi
authors.initials: J
authors.lastname: Zhou
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China duane@ioz.ac.cn.
authors.forename: Enkui
authors.initials: E
authors.lastname: Duan
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002352:Carrier Proteins / Q000494:pharmacology; D006197:Hair; D018859:Hair Follicle / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D012038:Regeneration; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000099176:Noggin Protein
chemical_list: D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D058570:TOR Serine-Threonine Kinases; D000099176:Noggin Protein
keywords: BMP; hair follicle; mTOR; skin; stem cells