Developmental YAPdeltaC determines adult pathology in a model of spinocerebellar ataxia type 1
Year: 2017
Type: article
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.
Source: Nature Communications
Authors: Kyota Fujita, Ying Mao, Shigenori Uchida, Xigui Chen, Hiroki Shiwaku, Takuya Tamura, Hikaru Ito, Kei Watase, Hidenori Homma, Kazuhiko Tagawa, Marius Sudol, Hitoshi Okazawa
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: Japan Agency for Medical Research and Development, Ministry of Education, Culture, Sports, Science and Technology, Tokyo Medical and Dental University, Foundation of Synapse and Neurocircuit Pathology, Japan Society for the Promotion of Science, Japan Science and Technology Agency, Core Research for Evolutional Science and Technology
Awards: Integrative understanding and therapeutic application of seamless degenerative processes based on Hippo pathway, G2521286739, G2576085165, G3115983120, Generation of myogenic stem cells from iPS cells via blastocyst complementation., G3875646562, G6006825254, G6200351348, G6718509927, G7879866177, G887906512
OpenAlex ID: W2769600758