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PLoS Genet. 2016 Jun 28;12(6):e1006129. doi: 10.1371/journal.pgen.1006129. eCollection 2016 Jun.

Misregulation of Alternative Splicing in a Mouse Model of Rett Syndrome.

Li R1,2, Dong Q2, Yuan X3, Zeng X4, Gao Y2, Chiao C2, Li H2,5, Zhao X2, Keles S4,6, Wang Z3,7, Chang Q1,2,5,8.

Author information

1
CMB Training Program, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
2
Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
3
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
4
Department of Statistics, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
5
Genetics Training Program, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
6
Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
7
Chinese Academy of Sciences (CAS) Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai, China.
8
Departments of Medical Genetics and Neurology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.

Abstract

Mutations in the human MECP2 gene cause Rett syndrome (RTT), a severe neurodevelopmental disorder that predominantly affects girls. Despite decades of work, the molecular function of MeCP2 is not fully understood. Here we report a systematic identification of MeCP2-interacting proteins in the mouse brain. In addition to transcription regulators, we found that MeCP2 physically interacts with several modulators of RNA splicing, including LEDGF and DHX9. These interactions are disrupted by RTT causing mutations, suggesting that they may play a role in RTT pathogenesis. Consistent with the idea, deep RNA sequencing revealed misregulation of hundreds of splicing events in the cortex of Mecp2 knockout mice. To reveal the functional consequence of altered RNA splicing due to the loss of MeCP2, we focused on the regulation of the splicing of the flip/flop exon of Gria2 and other AMPAR genes. We found a significant splicing shift in the flip/flop exon toward the flop inclusion, leading to a faster decay in the AMPAR gated current and altered synaptic transmission. In summary, our study identified direct physical interaction between MeCP2 and splicing factors, a novel MeCP2 target gene, and established functional connection between a specific RNA splicing change and synaptic phenotypes in RTT mice. These results not only help our understanding of the molecular function of MeCP2, but also reveal potential drug targets for future therapies.

PMID:
27352031
PMCID:
PMC4924826
DOI:
10.1371/journal.pgen.1006129
[Indexed for MEDLINE]
Free PMC Article

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