Misregulation of Alternative Splicing in a Mouse Model of Rett Syndrome.
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...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2016-06-01
|
| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC4924826?pdf=render |
| _version_ | 1828238272738885632 |
|---|---|
| author | Ronghui Li Qiping Dong Xinni Yuan Xin Zeng Yu Gao Cassandra Chiao Hongda Li Xinyu Zhao Sunduz Keles Zefeng Wang Qiang Chang |
| author_facet | Ronghui Li Qiping Dong Xinni Yuan Xin Zeng Yu Gao Cassandra Chiao Hongda Li Xinyu Zhao Sunduz Keles Zefeng Wang Qiang Chang |
| author_sort | Ronghui Li |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T21:01:00Z |
| format | Article |
| id | doaj.art-0f4911b265ba4da589e374416b596ab1 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-04-12T21:01:00Z |
| publishDate | 2016-06-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-0f4911b265ba4da589e374416b596ab12022-12-22T03:16:50ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042016-06-01126e100612910.1371/journal.pgen.1006129Misregulation of Alternative Splicing in a Mouse Model of Rett Syndrome.Ronghui LiQiping DongXinni YuanXin ZengYu GaoCassandra ChiaoHongda LiXinyu ZhaoSunduz KelesZefeng WangQiang ChangMutations 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.http://europepmc.org/articles/PMC4924826?pdf=render |
| spellingShingle | Ronghui Li Qiping Dong Xinni Yuan Xin Zeng Yu Gao Cassandra Chiao Hongda Li Xinyu Zhao Sunduz Keles Zefeng Wang Qiang Chang Misregulation of Alternative Splicing in a Mouse Model of Rett Syndrome. PLoS Genetics |
| title | Misregulation of Alternative Splicing in a Mouse Model of Rett Syndrome. |
| title_full | Misregulation of Alternative Splicing in a Mouse Model of Rett Syndrome. |
| title_fullStr | Misregulation of Alternative Splicing in a Mouse Model of Rett Syndrome. |
| title_full_unstemmed | Misregulation of Alternative Splicing in a Mouse Model of Rett Syndrome. |
| title_short | Misregulation of Alternative Splicing in a Mouse Model of Rett Syndrome. |
| title_sort | misregulation of alternative splicing in a mouse model of rett syndrome |
| url | http://europepmc.org/articles/PMC4924826?pdf=render |
| work_keys_str_mv | AT ronghuili misregulationofalternativesplicinginamousemodelofrettsyndrome AT qipingdong misregulationofalternativesplicinginamousemodelofrettsyndrome AT xinniyuan misregulationofalternativesplicinginamousemodelofrettsyndrome AT xinzeng misregulationofalternativesplicinginamousemodelofrettsyndrome AT yugao misregulationofalternativesplicinginamousemodelofrettsyndrome AT cassandrachiao misregulationofalternativesplicinginamousemodelofrettsyndrome AT hongdali misregulationofalternativesplicinginamousemodelofrettsyndrome AT xinyuzhao misregulationofalternativesplicinginamousemodelofrettsyndrome AT sunduzkeles misregulationofalternativesplicinginamousemodelofrettsyndrome AT zefengwang misregulationofalternativesplicinginamousemodelofrettsyndrome AT qiangchang misregulationofalternativesplicinginamousemodelofrettsyndrome |