Developmental YAPdeltaC determines adult pathology in a model of spinocerebellar ataxia type 1.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 29192206.
- Also identified by DOI 10.1038/s41467-017-01790-z and PMC identifier 5709507.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Adaptor Proteins, Signal Transducing
- Ataxin-1
- Cerebellum
- Gene Expression Regulation, Developmental
- Neurons
- Nuclear Receptor Subfamily 1, Group F, Member 1
- Phosphoproteins
- Spinocerebellar Ataxias