Muscleblind-like 2-Mediated Alternative Splicing in the Developing Brain and Dysregulation in Myotonic Dystrophy

Konstantinos Charizanis, Kuang Yung Lee, Ranjan Batra, Marianne Goodwin, Chaolin Zhang, Yuan Yuan, Lily Shiue, Melissa Cline, Marina M. Scotti, Guangbin Xia, Ashok Kumar, Tetsuo Ashizawa, H. Brent Clark, Takashi Kimura, Masanori P. Takahashi, Harutoshi Fujimura, Kenji Jinnai, Hiroo Yoshikawa, Mário Gomes-Pereira, Geneviève GourdonNoriaki Sakai, Seiji Nishino, Thomas C. Foster, Manuel Ares, Robert B. Darnell, Maurice S. Swanson*

*此作品的通信作者

研究成果: 期刊稿件文章同行評審

266 引文 (SciVal)

摘要

The RNA-mediated disease model for myotonic dystrophy (DM) proposes that microsatellite C(C)TG expansions express toxic RNAs that disrupt splicing regulation by altering MBNL1 and CELF1 activities. While this model explains DM manifestations in muscle, less is known about the effects of C(C)UG expression on the brain. Here, we report that Mbnl2 knockout mice develop several DM-associated central nervous system (CNS) features including abnormal REM sleep propensity and deficits in spatial memory. Mbnl2 is prominently expressed in the hippocampus and Mbnl2 knockouts show a decrease in NMDA receptor (NMDAR) synaptic transmission and impaired hippocampal synaptic plasticity. While Mbnl2 loss did not significantly alter target transcript levels in the hippocampus, misregulated splicing of hundreds of exons was detected using splicing microarrays, RNA-seq, and HITS-CLIP. Importantly, the majority of the Mbnl2-regulated exons examined were similarly misregulated in DM. We propose that major pathological features of the DM brain result from disruption of the MBNL2-mediated developmental splicing program.

原文英語
頁(從 - 到)437-450
頁數14
期刊Neuron
75
發行號3
DOIs
出版狀態已出版 - 09 08 2012
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