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发育性 YAPdeltaC 在脊髓小脑共济失调 1 型模型中决定成人病理学。

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

机构信息

Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.

Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.

出版信息

Nat Commun. 2017 Nov 30;8(1):1864. doi: 10.1038/s41467-017-01790-z.

DOI:10.1038/s41467-017-01790-z
PMID:29192206
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5709507/
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.

摘要

YAP 及其神经元同工型 YAPdeltaC 参与各种细胞功能。我们发现，在发育过程中而不是成年期表达 YAPdeltaC 可挽救突变型共济失调 1 敲入（Atxn1-KI）小鼠的神经退行性变表型。YAP/YAPdeltaC 通过第二个 WW 结构域与 RORα 相互作用，并作为其转录活性的共激活剂。YAP/YAPdeltaC 与 RORα 在靶基因的顺式元件上形成转录复合物，并调节其表达。正常和突变型 Atxn1 均与 YAP/YAPdeltaC 相互作用，但只有突变型 Atxn1 从 RORα 复合物中耗尽 YAP/YAPdeltaC，以在短时间尺度上抑制转录。在较长时间内，突变型 Atxn1 还会使体内的 RORα 减少。YAPdeltaC 的遗传补充恢复了 RORα 和 YAP/YAPdeltaC 的水平，恢复了 RORα 复合物中的 YAP/YAPdeltaC，并使 Atxn1-KI 小鼠体内的靶基因转录正常化。总之，我们的数据表明，突变型 Atxn1 在发育过程中对 YAP/YAPdeltaC 的功能障碍决定了 SCA1 的成年病理学，通过抑制 RORα 介导的转录。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b398/5709507/47727e317f41/41467_2017_1790_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b398/5709507/0ec1e606093b/41467_2017_1790_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b398/5709507/a4b8f0951e90/41467_2017_1790_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b398/5709507/8885e7434224/41467_2017_1790_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b398/5709507/7e5e4a4bd691/41467_2017_1790_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b398/5709507/ccad0a501628/41467_2017_1790_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b398/5709507/3d63750d227b/41467_2017_1790_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b398/5709507/d23684ff3d3c/41467_2017_1790_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b398/5709507/47727e317f41/41467_2017_1790_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b398/5709507/0ec1e606093b/41467_2017_1790_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b398/5709507/085d15869618/41467_2017_1790_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b398/5709507/17997b7d093a/41467_2017_1790_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b398/5709507/a4b8f0951e90/41467_2017_1790_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b398/5709507/8885e7434224/41467_2017_1790_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b398/5709507/7e5e4a4bd691/41467_2017_1790_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b398/5709507/ccad0a501628/41467_2017_1790_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b398/5709507/3d63750d227b/41467_2017_1790_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b398/5709507/d23684ff3d3c/41467_2017_1790_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b398/5709507/47727e317f41/41467_2017_1790_Fig10_HTML.jpg

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