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Between neurodevelopmental disorders and normal brain formation: Focusing on neuronal differentiation and migration as key milestones.

開催日 2014/9/13
時間 9:00 - 11:00
会場 Room F(302)
Chairperson(s) 川内 健史 / Takeshi Kawauchi (慶應義塾大学医学部生理学教室 / PRESTO, JST / Department of Physiology, Keio University School of Medicine, Japan)
小山 隆太 / Ryuta Koyama (東京大学大学院薬学系研究科薬品作用学教室 / Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan)

Molecular basis for the regulation of excitatory synaptic transmission by the Rett syndrome causative protein MeCP2

  • S3-F-1-3
  • 辻村 啓太 / Keita Tsujimura:1 入江 浩一郎 / Koichiro Irie:1 中嶋 秀行 / Hideyuki Nakashima:1 江頭 良明 / Yoshihiro Egashira:2 深尾 陽一郎 / Yoichiro Fukao:3 藤原 正幸 / Masayuki Fujiwara:3 伊藤 雅之 / Masayuki Ito:4 高森 茂雄 / Shigeo Takamori:2 中島 欽一 / Kinichi Nakashima:1 
  • 1:九州大院・医・基盤幹細胞 / Dept Stem cell biology and Medicine, Kyushu University, Fukuoka, Japan 2:同志社大院・脳科学・神経膜分子 / Lab of Neural membrane Biol, Doshisha Univ, Kyoto, Japan 3:奈良先端大バイオサイエンス・バイオ・植物グローバル教育プロジェクト / Plant Science Global Education Project, NAIST, Nara, Japan 4:国立精神・神経セ・神経研・疾病2部 / Dept Mental Retardation and Birth Defect Reserch, National Inst Neurosci, NCNP, Tokyo, Japan 

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the X-linked gene MECP2. Emerging evidence suggests that MeCP2 is a context-dependent regulator of gene expression, acting as a methylation-dependent transcriptional repressor, transcriptional activator and mRNA splicing regulator. However, direct MeCP2 targets, and the precise molecular mechanisms underlying RTT pathogenesis, remain obscure. We show here that MeCP2 unexpectedly facilitates the post-transcriptional processing of a particular microRNA (miRNA) as a component of the miRNA microprocessor Drosha complex. Surprisingly, introduction of this MeCP2-target miRNA (miR-MeCtgt) into MeCP2-deficient hippocampal neurons restored reduced soma size, excitatory synaptic formation and neurotransmission, which are hallmarks of RTT neuropathology. Moreover, inhibition of endogenous miR-MeCtgt recapitulated the RTT neuronal phenotype and abolished MeCP2 function both in vitro and in vivo, strongly suggesting that miR-MeCtgt acts downstream of MeCP2. We also found that expression of miR-MeCtgt is post-transcriptionally dysregulated in the frontal cortex of RTT individuals. These findings reveal a previously unrecognized function of MeCP2 in facilitation of miRNA processing and suggest that post-transcriptional regulation of miRNA biogenesis is involved in neuronal functions regulated by MeCP2, bringing us closer to understanding how MeCP2 deficiency leads to RTT pathogenesis.

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