MiR-199a Links MeCP2 with mTOR Signaling and Its Dysregulation Leads to Rett Syndrome Phenotypes

Keita Tsujimura, Koichiro Irie, Hideyuki Nakashima, Yoshihiro Egashira, Yoichiro Fukao, Masayuki Fujiwara, Masayuki Itoh, Masahiro Uesaka, Takuya Imamura, Yasukazu Nakahata, Yui Yamashita, Takaya Abe, Shigeo Takamori, Kinichi Nakashima

研究成果: ジャーナルへの寄稿記事

39 引用 (Scopus)

抄録

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.

元の言語英語
ページ(範囲)1887-1901
ページ数15
ジャーナルCell Reports
12
発行部数11
DOI
出版物ステータス出版済み - 9 22 2015

Fingerprint

Rett Syndrome
Sirolimus
Phenotype
MicroRNAs
Microcomputers
Microprocessor chips
Brain
Association reactions
Mutation
Processing

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

これを引用

MiR-199a Links MeCP2 with mTOR Signaling and Its Dysregulation Leads to Rett Syndrome Phenotypes. / Tsujimura, Keita; Irie, Koichiro; Nakashima, Hideyuki; Egashira, Yoshihiro; Fukao, Yoichiro; Fujiwara, Masayuki; Itoh, Masayuki; Uesaka, Masahiro; Imamura, Takuya; Nakahata, Yasukazu; Yamashita, Yui; Abe, Takaya; Takamori, Shigeo; Nakashima, Kinichi.

:: Cell Reports, 巻 12, 番号 11, 22.09.2015, p. 1887-1901.

研究成果: ジャーナルへの寄稿記事

Tsujimura, K, Irie, K, Nakashima, H, Egashira, Y, Fukao, Y, Fujiwara, M, Itoh, M, Uesaka, M, Imamura, T, Nakahata, Y, Yamashita, Y, Abe, T, Takamori, S & Nakashima, K 2015, 'MiR-199a Links MeCP2 with mTOR Signaling and Its Dysregulation Leads to Rett Syndrome Phenotypes', Cell Reports, 巻. 12, 番号 11, pp. 1887-1901. https://doi.org/10.1016/j.celrep.2015.08.028
Tsujimura K, Irie K, Nakashima H, Egashira Y, Fukao Y, Fujiwara M その他. MiR-199a Links MeCP2 with mTOR Signaling and Its Dysregulation Leads to Rett Syndrome Phenotypes. Cell Reports. 2015 9 22;12(11):1887-1901. https://doi.org/10.1016/j.celrep.2015.08.028
Tsujimura, Keita ; Irie, Koichiro ; Nakashima, Hideyuki ; Egashira, Yoshihiro ; Fukao, Yoichiro ; Fujiwara, Masayuki ; Itoh, Masayuki ; Uesaka, Masahiro ; Imamura, Takuya ; Nakahata, Yasukazu ; Yamashita, Yui ; Abe, Takaya ; Takamori, Shigeo ; Nakashima, Kinichi. / MiR-199a Links MeCP2 with mTOR Signaling and Its Dysregulation Leads to Rett Syndrome Phenotypes. :: Cell Reports. 2015 ; 巻 12, 番号 11. pp. 1887-1901.
@article{2a19ac2fff53477fb9a1e3c6977c7927,
title = "MiR-199a Links MeCP2 with mTOR Signaling and Its Dysregulation Leads to Rett Syndrome Phenotypes",
abstract = "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.",
author = "Keita Tsujimura and Koichiro Irie and Hideyuki Nakashima and Yoshihiro Egashira and Yoichiro Fukao and Masayuki Fujiwara and Masayuki Itoh and Masahiro Uesaka and Takuya Imamura and Yasukazu Nakahata and Yui Yamashita and Takaya Abe and Shigeo Takamori and Kinichi Nakashima",
year = "2015",
month = "9",
day = "22",
doi = "10.1016/j.celrep.2015.08.028",
language = "English",
volume = "12",
pages = "1887--1901",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "11",

}

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

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.

UR - http://www.scopus.com/inward/record.url?scp=84942832697&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84942832697&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2015.08.028

DO - 10.1016/j.celrep.2015.08.028

M3 - Article

C2 - 26344767

AN - SCOPUS:84942832697

VL - 12

SP - 1887

EP - 1901

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 11

ER -