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

被引：265

作者：

Charizanis, Konstantinos ^{[1
,16
]}

Lee, Kuang-Yung ^{[1
,4
,16
]}

Batra, Ranjan ^{[1
,16
]}

Goodwin, Marianne ^{[1
,16
]}

Zhang, Chaolin ^{[5
,6
]}

Yuan, Yuan ^{[5
,6
]}

Shiue, Lily ^{[7
]}

Cline, Melissa ^{[7
]}

Scotti, Marina M. ^{[1
,16
]}

Xia, Guangbin ^{[2
]}

Kumar, Ashok ^{[3
]}

Ashizawa, Tetsuo ^{[2
]}

Clark, H. Brent ^{[8
,9
]}

Kimura, Takashi ^{[10
]}

Takahashi, Masanori P. ^{[11
]}

Fujimura, Harutoshi ^{[12
]}

Jinnai, Kenji ^{[13
]}

Yoshikawa, Hiroo ^{[10
]}

Gomes-Pereira, Mario ^{[14
]}

Gourdon, Genevieve ^{[14
]}

Sakai, Noriaki ^{[15
]}

Nishino, Seiji ^{[15
]}

Foster, Thomas C. ^{[3
]}

Ares, Manuel, Jr. ^{[7
]}

Darnell, Robert B. ^{[5
,6
]}

Swanson, Maurice S. ^{[1
,16
]}

机构：

[1] Univ Florida, Coll Med, Dept Mol Genet & Microbiol, Gainesville, FL 32610 USA

[2] Univ Florida, Coll Med, Dept Neurol, Gainesville, FL 32610 USA

[3] Univ Florida, Coll Med, Dept Neurosci, Gainesville, FL 32610 USA

[4] Chang Gung Mem Hosp, Dept Neurol, Keelung 204, Taiwan

[5] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA

[6] Rockefeller Univ, Mol Neurooncol Lab, New York, NY 10065 USA

[7] Univ Calif Santa Cruz, Dept Mol,Cell & Dev Biol, Santa Cruz, CA 95064 USA

[8] Univ Minnesota, Sch Med, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA

[9] Univ Minnesota, Sch Med, Dept Neurol & Neurosurg, Minneapolis, MN 55455 USA

[10] Hyogo Coll Med, Dept Internal Med, Div Neurol, Nishinomiya, Hyogo 6638501, Japan

[11] Osaka Univ, Grad Sch Med, Dept Neurol, Suita, Osaka 5650871, Japan

[12] Natl Hosp Org, Toneyama Hosp, Dept Neurol, Osaka 5608552, Japan

[13] Natl Hosp Org, Hyogo Chuo Hosp, Dept Neurol, Hyogo 6691592, Japan

[14] Univ Paris 05, Hop Necker Enfants Malad, INSERM, U781,Fondat IMAGINE, Paris 15, France

[15] Stanford Univ, Sch Med, Stanford Sleep & Circadian Neurobiol Lab, Palo Alto, CA 94304 USA

[16] Univ Florida, Coll Med, Ctr NeuroGenet, Gainesville, FL 32610 USA

来源：

NEURON | 2012年 / 75卷 / 03期

关键词：

HEXANUCLEOTIDE REPEAT; RNA INTERACTIONS; OVEREXPRESSION; INSIGHTS; CUGBP1; MODEL; REVEALS; C9ORF72; SYSTEM; MEMORY;

D O I：

10.1016/j.neuron.2012.05.029

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

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.

引用

页码：437 / 450

页数：14

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