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Developmental YAPdeltaC determines adult pathology in a model of spinocerebellar ataxia type 1.
Fujita, Kyota; Mao, Ying; Uchida, Shigenori; Chen, Xigui; Shiwaku, Hiroki; Tamura, Takuya; Ito, Hikaru; Watase, Kei; Homma, Hidenori; Tagawa, Kazuhiko; Sudol, Marius; Okazawa, Hitoshi.
Affiliation
  • Fujita K; Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
  • Mao Y; Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
  • Uchida S; Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
  • Chen X; Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
  • Shiwaku H; Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
  • Tamura T; Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
  • Ito H; Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
  • Watase K; Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
  • Homma H; Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
  • Tagawa K; Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
  • Sudol M; Mechanobiology Institute, National University of Singapore, 5A Engineering Drive 1, Singapore, 117411, Singapore.
  • Okazawa H; Department of Physiology, National University of Singapore, Yong Loo Li School of Medicine, 2 Medical Drive, Singapore, 117597, Singapore.
Nat Commun ; 8(1): 1864, 2017 11 30.
Article in En | MEDLINE | ID: mdl-29192206
YAP and its neuronal isoform YAPdeltaC are implicated in various cellular functions. We found that expression of YAPdeltaC during development, but not adulthood, rescued neurodegeneration phenotypes of mutant ataxin-1 knock-in (Atxn1-KI) mice. YAP/YAPdeltaC interacted with RORα via the second WW domain and served as co-activators of its transcriptional activity. YAP/YAPdeltaC formed a transcriptional complex with RORα on cis-elements of target genes and regulated their expression. Both normal and mutant Atxn1 interacted with YAP/YAPdeltaC, but only mutant Atxn1 depleted YAP/YAPdeltaC from the RORα complex to suppress transcription on short timescales. Over longer periods, mutant Atxn1 also decreased RORα in vivo. Genetic supplementation of YAPdeltaC restored the RORα and YAP/YAPdeltaC levels, recovered YAP/YAPdeltaC in the RORα complex and normalized target gene transcription in Atxn1-KI mice in vivo. Collectively, our data suggest that functional impairment of YAP/YAPdeltaC by mutant Atxn1 during development determines the adult pathology of SCA1 by suppressing RORα-mediated transcription.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Phosphoproteins / Cerebellum / Gene Expression Regulation, Developmental / Spinocerebellar Ataxias / Adaptor Proteins, Signal Transducing / Nuclear Receptor Subfamily 1, Group F, Member 1 / Ataxin-1 / Neurons Limits: Animals Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2017 Document type: Article Affiliation country: Japan Country of publication: United kingdom
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Phosphoproteins / Cerebellum / Gene Expression Regulation, Developmental / Spinocerebellar Ataxias / Adaptor Proteins, Signal Transducing / Nuclear Receptor Subfamily 1, Group F, Member 1 / Ataxin-1 / Neurons Limits: Animals Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2017 Document type: Article Affiliation country: Japan Country of publication: United kingdom