RhoGEF Trio Regulates Radial Migration of Projection Neurons via Its Distinct Domains
RhoGEF Trio 通过其不同的域调节投射神经元的径向迁移
RhoGEF Trioは、その別個のドメインを介して投射ニューロンの放射状移動を調節します
RhoGEF Trio는 고유한 영역을 통해 투영 뉴런의 방사형 마이그레이션을 조절합니다
RhoGEF Trio regula la migración radial de las neuronas de proyección a través de sus distintos dominios
RhoGEF Trio régule la migration radiale des neurones de projection via ses domaines distincts
RhoGEF Trio регулирует радиальную миграцию проекционных нейронов через свои отдельные домены
Chengwen Wei ¹, Mengwen Sun ¹ ², Xiaoxuan Sun ¹, Hu Meng ¹, Qiongwei Li ¹, Kai Gao 高凯 ¹, Weihua Yue 岳伟华 ¹ ³, Lifang Wang 王力芳 ¹, Dai Zhang 张岱 ¹ ⁴ ⁵, Jun Li 李俊 ¹
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
中国 北京 北京大学第六医院 北京大学精神卫生研究所 国家卫生健康委员会精神卫生学重点实验室（北京大学） 国家精神心理疾病临床医学研究中心（北京大学第六医院）
² Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China
中国 北京 清华大学-北京大学生命科学联合中心
³ PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, 100871, China
中国 北京 北京大学IDG麦戈文脑科学研究所
⁴ Chinese Institute for Brain Research, Beijing, 100010, China
中国 北京 北京脑科学与类脑研究中心
⁵ Institute for Brain Research and Rehabilitation (IBRR), Guangdong Key Laboratory of Mental Health and Cognitive Science, South China Normal University, Guangzhou, 510631, China
华南师范大学 广东省心理健康与认知科学重点实验室 脑科学与康复医学研究院
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.
