Cachd1 interacts with Wnt receptors and regulates neuronal asymmetry in the zebrafish brain

• 成果类型: Article
• 署名作者: Powell, Gareth T.; Faro, Ana; Zhao, Yuguang; Stickney, Heather; Novellasdemunt, Laura; Henriques, Pedro; Gestri, Gaia; White, Esther Redhouse; Ren, Jingshan; Lu, Weixian; Young, Rodrigo M.; Hawkins, Thomas A.; Cavodeassi, Florencia; Schwarz, Quenten; Dreosti, Elena; Raible, David W.; Li, Vivian S. W.; Wright, Gavin J.; Jones, E. Yvonne; Wilson, Stephen W.
• 署名单位: University of London; University College London; Wellcome Trust Sanger Institute; University of Oxford; Wellcome Centre for Human Genetics; University of Washington; University of Washington Seattle; Francis Crick Institute; Barcelona Institute of Science & Technology; Institute for Research in Biomedicine - IRB Barcelona; University of London; University College London; Universidad Mayor; City St Georges, University of London; University of Hull; University of York - UK
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12234
• DOI: 10.1126/science.ade6970
• 发表日期: 2024-05-03
• 页码: 573-579
• 关键词: structural basis; protein; expression; inhibition; complex; binding; lrp6; morphogenesis; Visualization; neurogenesis

摘要

Neurons on the left and right sides of the nervous system often show asymmetric properties, but how such differences arise is poorly understood. Genetic screening in zebrafish revealed that loss of function of the transmembrane protein Cachd1 resulted in right-sided habenula neurons adopting left-sided identity. Cachd1 is expressed in neuronal progenitors, functions downstream of asymmetric environmental signals, and influences timing of the normally asymmetric patterns of neurogenesis. Biochemical and structural analyses demonstrated that Cachd1 can bind simultaneously to Lrp6 and Frizzled family Wnt co-receptors. Consistent with this, lrp6 mutant zebrafish lose asymmetry in the habenulae, and epistasis experiments support a role for Cachd1 in modulating Wnt pathway activity in the brain. These studies identify Cachd1 as a conserved Wnt receptor-interacting protein that regulates lateralized neuronal identity in the zebrafish brain.