RhoGEF Trio Regulates Radial Migration of Projection Neurons via Its Distinct Domains  

作　　者：Chengwen Wei Mengwen Sun Xiaoxuan Sun Hu Meng Qiongwei Li Kai Gao Weihua Yue Lifang Wang Dai Zhang Jun Li 

机构地区：[1]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

出　　处：《Neuroscience Bulletin》2022年第3期249-262,共14页神经科学通报（英文版）

基　　金：the Key Realm R&D Program of Guangdong Province(2019B030335001);the National Key R&D Program of China(2016YFC1307000);the National Natural Science Foundation of China(81730037,81825009,81871077,81671363,and 82071541);the Beijing Major Science and Technology Projects(Z181100001518001).

摘　　要：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.

关 键 词：TRIO Myosin X RHOGEF NEURODEVELOPMENTAL DISORDER Radial migration 

分 类 号：R338[医药卫生—人体生理学]