Misregulation of Alternative Splicing in a Mouse Model of Rett Syndrome

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  • Li, Ronghui
    • Other Affiliation: CMB Training Program; University of Wisconsin-Madison
  • Dong, Qiping
    • Other Affiliation: Waisman Center; University of Wisconsin-Madison
  • Yuan, Xinni
    • Affiliation: School of Medicine, Department of Pharmacology
  • Zeng, Xin
    • Other Affiliation: Department of Statistics; University of Wisconsin-Madison
  • Gao, Yu
    • Other Affiliation: Waisman Center; University of Wisconsin-Madison
  • Chiao, Cassandra
    • ORCID: 0000-0003-4186-0667
    • Other Affiliation: Waisman Center; University of Wisconsin-Madison
  • Li, Hongda
    • Other Affiliation: Genetics Training Program; University of Wisconsin-Madison
  • Zhao, Xinyu
    • ORCID: 0000-0002-5128-4424
    • Other Affiliation: Waisman Center; University of Wisconsin-Madison
  • Keles, Sunduz
    • Other Affiliation: Department of Biostatistics and Medical Informatics; University of Wisconsin-Madison
  • Wang, Zefeng
    • Affiliation: School of Medicine, Department of Pharmacology
    • Other Affiliation: Chinese Academy of Sciences (CAS) Key Laboratory of Computational Biology; CAS-MPG Partner Institute for Computational Biology
  • Chang, Qiang
    • Other Affiliation: Genetics Training Program; University of Wisconsin-Madison
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.
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  • Article
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  • In Copyright
Journal title
  • PLoS Genetics
Journal volume
  • 12
Journal issue
  • 6
Page start
  • e1006129
Language
  • English
ISSN
  • 1553-7390
  • 1553-7404

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