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 neurodevelopme...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.展开更多
Domain insertions and deletions lead to variations in the domain architectures of the proteins from their common ancestor. In this work, we investigated four groups of the RhoGEF-containing proteins from different org...Domain insertions and deletions lead to variations in the domain architectures of the proteins from their common ancestor. In this work, we investigated four groups of the RhoGEF-containing proteins from different organisms with domain architectures RhoGEF-PH-SH3, SH3-RhoGEF-PH, RhoGEF-PH, and SH3-RhoGEF defined in the Pfam database. The phylogenetic trees were constructed using each individual domain and/or the combinations of all the domains. The phylogenetic analysis suggests that RhoGEF-PH-SH3 and SH3-RhoGEF-PH might have evolved from RhoGEF-PH through the insertion of SH3 independently, while SH3- RhoGEF of proteins in fruit fly might have evolved from SH3-RhoGEF-PH by the degeneration of PH domain.展开更多
基金the Key Realm R&D Program of Guangdong Province(2019B030335001)the National Key R&D Program of China(2016YFC1307000)+1 种基金the National Natural Science Foundation of China(81730037,81825009,81871077,81671363,and 82071541)the Beijing Major Science and Technology Projects(Z181100001518001).
文摘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.
基金We thank anonymous reviewers for their helpful comments.This work was supported by the National High-Tech Research and Development Program of China(Grant No.2003AA231030)the Excellent Young Teachers Program of the Ministry of Education of China(2003),and Beijing Normal University.
文摘Domain insertions and deletions lead to variations in the domain architectures of the proteins from their common ancestor. In this work, we investigated four groups of the RhoGEF-containing proteins from different organisms with domain architectures RhoGEF-PH-SH3, SH3-RhoGEF-PH, RhoGEF-PH, and SH3-RhoGEF defined in the Pfam database. The phylogenetic trees were constructed using each individual domain and/or the combinations of all the domains. The phylogenetic analysis suggests that RhoGEF-PH-SH3 and SH3-RhoGEF-PH might have evolved from RhoGEF-PH through the insertion of SH3 independently, while SH3- RhoGEF of proteins in fruit fly might have evolved from SH3-RhoGEF-PH by the degeneration of PH domain.
基金This work was supported by the Bioteclmology and Functional genomics(FUGE)programs of the Norwegian Research Council through grants NFR 159959,164583 and 151991(T B,P W and A M B)by grants from the National Science Foundation,the Department of Energy and the US Department of Agriculture(Z Y).
