Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Cell reports (Cambridge), 2015-09, Vol.12 (11), p.1887-1901

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2015

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •MeCP2 facilitates the processing of miR-199a as a component of the Drosha complex•miR-199a ameliorates RTT neuronal phenotypes and its inhibition blocks MeCP2 function•miR-199a positively controls mTOR signaling by targeting mTOR signaling inhibitors•Genetic deletion of miR-199a-2 recapitulates numerous RTT phenotypes Tsujimura et al. find that MeCP2 facilitates processing of miR-199a, which, in turn, leads to upregulation of mTOR signaling. Genetic deletion of miR-199a-2 recapitulates RTT phenotypes, suggesting that the MeCP2/miR-199a/mTOR axis may contribute to RTT pathophysiology.