TY - JOUR
T1 - MiR-199a Links MeCP2 with mTOR Signaling and Its Dysregulation Leads to Rett Syndrome Phenotypes
AU - Tsujimura, Keita
AU - Irie, Koichiro
AU - Nakashima, Hideyuki
AU - Egashira, Yoshihiro
AU - Fukao, Yoichiro
AU - Fujiwara, Masayuki
AU - Itoh, Masayuki
AU - Uesaka, Masahiro
AU - Imamura, Takuya
AU - Nakahata, Yasukazu
AU - Yamashita, Yui
AU - Abe, Takaya
AU - Takamori, Shigeo
AU - Nakashima, Kinichi
N1 - Funding Information:
We thank H. Sasaki, H. Tou, H. Suzuki, K. Yanagitani, and K. Miyake for technical advice and reagents. We also thank K. Kohno, K. Miyazono, M.E. Greenberg, Z. Zhou, and T. Kubota for sharing reagents and cells, I. Smith for editing the manuscript, and all members of the Department of Stem Cell Biology and Medicine, Kyushu University, of the Laboratory of Molecular Neuroscience, of the Laboratory of Gene Regulation Research, Nara Institute of Science and Technology (NAIST), and of the Laboratory of Neural Membrane Biology, Doshisha University for assistance. We appreciate the technical assistance from The Research Support Center, Kyushu University. We are grateful to the Harvard Brain Tissue Resource Center for providing RTT samples. This work was supported in part by a Grant-in-Aid for Scientific Research (grant no. 24240051), a Grant-in-Aid for Scientific Research on Innovative Area: Foundation of Synapse and Neurocircuit Pathology, and the NAIST Global COE Program (Frontier biosciences: strategies for survival and adaptation in a changing global environment), all from the Ministry of Education, Culture, Sports, Science and Technology of Japan; and by an Intramural Research Grant (24-12) for Neurological and Psychiatric Disorders of NCNP. This work was partly performed in the Cooperative Research Project Program of the Medical Institute of Bioregulation, Kyushu University.
Publisher Copyright:
© 2015 The Authors.
PY - 2015/9/22
Y1 - 2015/9/22
N2 - 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.
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.
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U2 - 10.1016/j.celrep.2015.08.028
DO - 10.1016/j.celrep.2015.08.028
M3 - Article
C2 - 26344767
AN - SCOPUS:84942832697
SN - 2211-1247
VL - 12
SP - 1887
EP - 1901
JO - Cell Reports
JF - Cell Reports
IS - 11
ER -