title: Misregulation of Alternative Splicing in a Mouse Model of Rett Syndrome.
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.
authors.affiliation: CMB Training Program, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Ronghui
authors.initials: R
authors.lastname: Li
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Qiping
authors.initials: Q
authors.lastname: Dong
authors.affiliation: Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Xinni
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Department of Statistics, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Xin
authors.initials: X
authors.lastname: Zeng
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Yu
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Cassandra
authors.identifier: 0000-0003-4186-0667
authors.initials: C
authors.lastname: Chiao
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Genetics Training Program, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Hongda
authors.initials: H
authors.lastname: Li
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Xinyu
authors.identifier: 0000-0002-5128-4424
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Statistics, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Sunduz
authors.initials: S
authors.lastname: Keles
authors.affiliation: Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.|Chinese Academy of Sciences (CAS) Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai, China.
authors.forename: Zefeng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: CMB Training Program, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Genetics Training Program, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Departments of Medical Genetics and Neurology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Chang
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D005091:Exons / Q000235:genetics; D005260:Female; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D012313:RNA / Q000235:genetics; D015518:Rett Syndrome / Q000235:genetics*
chemical_list: D051783:Methyl-CpG-Binding Protein 2; D012313:RNA