Developmental YAPdeltaC determines adult pathology in a model of spinocerebellar ataxia type 1

Kyota Fujita, Ying Mao, Shigenori Uchida, Xigui Chen, Hiroki Shiwaku, Takuya Tamura, Hikaru Ito, Kei Watase, Hidenori Homma, Kazuhiko Tagawa, Marius Sudol and Hitoshi Okazawa ()
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Kyota Fujita: Tokyo Medical and Dental University
Ying Mao: Tokyo Medical and Dental University
Shigenori Uchida: Tokyo Medical and Dental University
Xigui Chen: Tokyo Medical and Dental University
Hiroki Shiwaku: Tokyo Medical and Dental University
Takuya Tamura: Tokyo Medical and Dental University
Hikaru Ito: Tokyo Medical and Dental University
Kei Watase: Tokyo Medical and Dental University
Hidenori Homma: Tokyo Medical and Dental University
Kazuhiko Tagawa: Tokyo Medical and Dental University
Marius Sudol: National University of Singapore
Hitoshi Okazawa: Tokyo Medical and Dental University

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-01790-z

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