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mTOR signaling promotes stem cell activation via counterbalancing BMP-mediated suppression during hair regeneration Free
Zhili Deng1,2,†, Xiaohua Lei1,†, Xudong Zhang1,2, Huishan Zhang1,2, Shuang Liu1, Qi Chen1, Huimin Hu1, Xinyue Wang1,2, Lina Ning1, Yujing Cao1, Tongbiao Zhao1, Jiaxi Zhou3, Ting Chen4, and Enkui Duan1,*
1State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
2University of Chinese Academy of Sciences, Beijing 100190, China
3State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
4National Institute of Biological Sciences, Beijing 102206, China *Correspondence to:Enkui Duan, E-mail: duane@ioz.ac.cn
J Mol Cell Biol, Volume 7, Issue 1, February 2015, Pages 62-72  https://doi.org/10.1093/jmcb/mjv005
Keyword: mTOR, skin, hair follicle, stem cells, BMP

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.