miR-199a Links MeCP2 with mTOR Signaling and Its Dysregulation Leads to Rett Syndrome Phenotypes.
miR-199a Links MeCP2 with mTOR Signaling and Its Dysregulation Leads to Rett Syndrome Phenotypes.
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DOI：
10.1016/j.celrep.2015.08.028
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发表时间：
2015-09
期刊：
影响因子：
8.8
通讯作者：
Keita Tsujimura;K. Irie;Hideyuki Nakashima;Y. Egashira;Y. Fukao;Masayuki Fujiwara;M. Itoh;Masahiro Uesaka;T. Imamura;Yasukazu Nakahata;Yui Yamashita;T. Abe;S. Takamori;K. Nakashima
中科院分区：
文献类型：
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作者：
Keita Tsujimura;K. Irie;Hideyuki Nakashima;Y. Egashira;Y. Fukao;Masayuki Fujiwara;M. Itoh;Masahiro Uesaka;T. Imamura;Yasukazu Nakahata;Yui Yamashita;T. Abe;S. Takamori;K. Nakashima
雷特综合征（RTT）是一种由 MECP2 突变引起的神经发育障碍。尽管新的证据表明 MeCP2 缺乏与雷帕霉素靶点 (mTOR) 的失调相关，而雷帕霉素靶点是各种信号通路的枢纽，但这种关联的机制和 RTT 的分子病理生理学仍然难以捉摸。我们在此表明，MeCP2 作为微处理器 Drosha 复合体的一个组成部分，可促进特定 microRNA (miRNA) 的转录后加工。在 MeCP2 调节的 miRNA 中，我们发现 miR-199a 通过靶向 mTOR 信号传导抑制剂来正向控制 mTOR 信号传导。 miR-199a 及其靶标对 mTOR 活性具有相反的作用，分别改善和诱导 RTT 神经元表型。此外，miR-199a-2 的基因缺失导致大脑中 mTOR 活性的降低，并在小鼠中重现了许多 RTT 表型。总之，这些发现通过将 MeCP2 与 mTOR 信号传导联系起来，确立了 miR-199a 作为 RTT 发病机制中 MeCP2 的关键下游靶标。
Rett syndrome (RTT) is a neurodevelopmental disorder caused byMECP2mutations. 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 ofmiR-199a-2led 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.