Fujita, K., Mao, Y., Uchida, S. et al. Developmental YAPdeltaC determines adult pathology in a model of spinocerebellar ataxia type 1. Nat Commun 8, 1864 (2017). https://doi.org/10.1038/s41467-017-01790-z
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.
License type:
http://creativecommons.org/licenses/by/4.0/
Funding Info:
This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas (Foundation of Synapse and Neurocircuit Pathology, 22110001 and 22110002) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, a Grant-in-Aid for Scientific Research (A) (16H02655) from Japan Society for Promotion of Science (JSPS), partly Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS) and Strategic Research Program for Brain Sciences (SRPBS) from Japan Agency for Medical Research and Development (AMED), a CREST grant from Japan Science and Technology Agency (JST) and grants for research on intractable diseases from AMED (to H.O.)