Elucidation of a novel mechanism relevant to disruption of microRNA biogenesis, explaining neurodevelopmental diseases.

2015 Fiscal Year Final Research Report

• Project/Area Number: 24240051
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neuroscience in general
• Research Institution: Kyushu University (2013-2015); Nara Institute of Science and Technology (2012)
• Principal Investigator: Nakashima Kinichi 九州大学, 医学(系)研究科(研究院), 教授 (80302892)
• Co-Investigator(Renkei-kenkyūsha): TSUJIMURA Keita 九州大学, 大学院医学研究院, 特任助教 (60588474) ; FUKAO Yoichiro 奈良先端科学技術大学院大学, バイオサイエンス研究科 (80432590)
• Project Period (FY): 2012-05-31 – 2016-03-31
• Keywords: 神経科学 / レット症候群 / MeCP2 / エピジェネティクス / マイクロRNA

Outline of Final Research Achievements

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 effect 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.

Free Research Field

神経科学