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

Author

Listed:
  • 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
    National University of Singapore, Yong Loo Li School of Medicine
    Institute of Molecular and Cell Biology (IMCB) A*STAR, Biopolis)

  • Hitoshi Okazawa

    (Tokyo Medical and Dental University
    Tokyo Medical and Dental University)

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.

Suggested Citation

  • Kyota Fujita & Ying Mao & Shigenori Uchida & Xigui Chen & Hiroki Shiwaku & Takuya Tamura & Hikaru Ito & Kei Watase & Hidenori Homma & Kazuhiko Tagawa & Marius Sudol & Hitoshi Okazawa, 2017. "Developmental YAPdeltaC determines adult pathology in a model of spinocerebellar ataxia type 1," Nature Communications, Nature, vol. 8(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01790-z
    DOI: 10.1038/s41467-017-01790-z
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