Chengwen Wei1 • Mengwen Sun1,2 • Xiaoxuan Sun1 • Hu Meng1 • Qiongwei Li1 • Kai Gao1 • Weihua Yue1,3 • Lifang Wang1 • Dai Zhang1,4,5 • Jun Li11 Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing 100191, China
2 Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
3 PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China
4 Chinese Institute for Brain Research, Beijing 100010, China
5 Institute for Brain Research and Rehabilitation (IBRR), Guangdong Key Laboratory of Mental Health and Cognitive Science, South China Normal University, Guangzhou 510631, China
Abstract
The radial migration of cortical pyramidal neurons (PNs) during corticogenesis is necessary for establishing a multilayered cerebral cortex. Neuronal migration defects are considered a critical etiology of neurodevelopmental disorders, including autism spectrum disorders (ASDs), schizophrenia, epilepsy, and intellectual disability (ID). TRIO is a high-risk candidate gene for ASDs and ID. However, its role in embryonic radial migration and the etiology of ASDs and ID are not fully understood. In this study, we found that the in vivo conditional knockout or in utero knockout of Trio in excitatory precursors in the neocortex caused aberrant polarity and halted the migration of late-born PNs. Further investigation of the underlying mechanism revealed that the interaction of the Trio N-terminal SH3 domain with Myosin X mediated the adherence of migrating neurons to radial glial fibers through regulating the membrane location of neuronal cadherin (N-cadherin). Also, independent or synergistic overexpression of RAC1 and RHOA showed different phenotypic recoveries of the abnormal neuronal migration by affecting the morphological transition and/or the glial fiber-dependent locomotion. Taken together, our findings clarify a novel mechanism of Trio in regulating N-cadherin cell surface expression via the interaction of Myosin X with its N-terminal SH3 domain. These results suggest the vital roles of the guanine nucleotide exchange factor 1 (GEF1) and GEF2 domains in regulating radial migration by activating their Rho GTPase effectors in both distinct and cooperative manners, which might be associated with the abnormal phenotypes in neurodevelopmental disorders.
Keywords
Trio; Myosin X; RhoGEF; Neurodevelopmental disorder; Radial migration
