PMID- 26344767 OWN - NLM STAT- MEDLINE DCOM- 20160706 LR - 20211203 IS - 2211-1247 (Electronic) VI - 12 IP - 11 DP - 2015 Sep 22 TI - miR-199a Links MeCP2 with mTOR Signaling and Its Dysregulation Leads to Rett Syndrome Phenotypes. PG - 1887-901 LID - S2211-1247(15)00899-2 [pii] LID - 10.1016/j.celrep.2015.08.028 [doi] AB - Rett syndrome (RTT) is a neurodevelopmental disorder caused by MECP2 mutations. Although emerging evidence suggests that MeCP2 deficiency is associated with dysregulation of mechanistic target of rapamycin (mTOR), which functions as a hub for various signaling pathways, the mechanism underlying this association and the molecular pathophysiology of RTT remain elusive. We show here that MeCP2 promotes the posttranscriptional processing of particular microRNAs (miRNAs) as a component of the microprocessor Drosha complex. Among the MeCP2-regulated miRNAs, we found that miR-199a positively controls mTOR signaling by targeting inhibitors for mTOR signaling. miR-199a and its targets have opposite effects on mTOR activity, ameliorating and inducing RTT neuronal phenotypes, respectively. Furthermore, genetic deletion of miR-199a-2 led to a reduction of mTOR activity in the brain and recapitulated numerous RTT phenotypes in mice. Together, these findings establish miR-199a as a critical downstream target of MeCP2 in RTT pathogenesis by linking MeCP2 with mTOR signaling. CI - Copyright (c) 2015 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Tsujimura, Keita AU - Tsujimura K AD - Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan; Laboratory of Molecular Neuroscience, Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0101, Japan. FAU - Irie, Koichiro AU - Irie K AD - Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan. FAU - Nakashima, Hideyuki AU - Nakashima H AD - Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan. FAU - Egashira, Yoshihiro AU - Egashira Y AD - Laboratory of Neural Membrane Biology, Graduate School of Brain Science, Doshisha University, 1-3 Miyakodani, Tatara, Kyotanabe, Kyoto 610-0394, Japan. FAU - Fukao, Yoichiro AU - Fukao Y AD - Plant Global Education Project, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0101, Japan; Department of Bioinformatics, Ritsumeikan University, Kusatsu, Shiga 525-8577, Japan. FAU - Fujiwara, Masayuki AU - Fujiwara M AD - Plant Global Education Project, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0101, Japan; Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0017, Japan. FAU - Itoh, Masayuki AU - Itoh M AD - Department of Mental Retardation and Birth Defect Research, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan. FAU - Uesaka, Masahiro AU - Uesaka M AD - Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan. FAU - Imamura, Takuya AU - Imamura T AD - Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan. FAU - Nakahata, Yasukazu AU - Nakahata Y AD - Laboratory of Gene Regulation Research, Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0101, Japan. FAU - Yamashita, Yui AU - Yamashita Y AD - Animal Resource Development Unit, RIKEN Center for Life Science Technologies, 2-2-3 Minatojima Minami-machi, Chuou-ku, Kobe 650-0047, Japan. FAU - Abe, Takaya AU - Abe T AD - Genetic Engineering Team, RIKEN Center for Life Science Technologies, 2-2-3 Minatojima Minami-machi, Chuou-ku, Kobe 650-0047, Japan. FAU - Takamori, Shigeo AU - Takamori S AD - Laboratory of Neural Membrane Biology, Graduate School of Brain Science, Doshisha University, 1-3 Miyakodani, Tatara, Kyotanabe, Kyoto 610-0394, Japan. FAU - Nakashima, Kinichi AU - Nakashima K AD - Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan; Laboratory of Molecular Neuroscience, Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0101, Japan. Electronic address: kin1@scb.med.kyushu-u.ac.jp. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150903 PL - United States TA - Cell Rep JT - Cell reports JID - 101573691 RN - 0 (Mecp2 protein, mouse) RN - 0 (Methyl-CpG-Binding Protein 2) RN - 0 (MicroRNAs) RN - 0 (Mirn199 microRNA, mouse) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 3.1.26.3 (Drosha protein, mouse) RN - EC 3.1.26.3 (Ribonuclease III) SB - IM MH - Animals MH - Disease Models, Animal MH - Methyl-CpG-Binding Protein 2/antagonists & inhibitors/genetics/*metabolism MH - Mice MH - Mice, Knockout MH - MicroRNAs/antagonists & inhibitors/genetics/*metabolism MH - Phenotype MH - Rett Syndrome/genetics/*metabolism MH - Ribonuclease III/genetics/metabolism MH - Signal Transduction MH - TOR Serine-Threonine Kinases/genetics/*metabolism MH - Up-Regulation EDAT- 2015/09/08 06:00 MHDA- 2016/07/07 06:00 CRDT- 2015/09/08 06:00 PHST- 2013/08/02 00:00 [received] PHST- 2015/06/06 00:00 [revised] PHST- 2015/08/08 00:00 [accepted] PHST- 2015/09/08 06:00 [entrez] PHST- 2015/09/08 06:00 [pubmed] PHST- 2016/07/07 06:00 [medline] AID - S2211-1247(15)00899-2 [pii] AID - 10.1016/j.celrep.2015.08.028 [doi] PST - ppublish SO - Cell Rep. 2015 Sep 22;12(11):1887-901. doi: 10.1016/j.celrep.2015.08.028. Epub 2015 Sep 3.