Inhibition of Foxp4 Disrupts Cadherin-based Adhesion of Radial Glial Cells, Leading to Abnormal Differentiation and Migration of Cortical Neurons in Mice / 神经科学通报·英文版

Heterozygous loss-of-function variants of FOXP4 are associated with neurodevelopmental disorders (NDDs) that exhibit delayed speech development, intellectual disability, and congenital abnormalities. The etiology of NDDs is unclear. Here we found that FOXP4 and N-cadherin are expressed in the nuclei and apical end-feet of radial glial cells (RGCs), respectively, in the mouse neocortex during early gestation. Knockdown or dominant-negative inhibition of Foxp4 abolishes the apical condensation of N-cadherin in RGCs and the integrity of neuroepithelium in the ventricular zone (VZ). Inhibition of Foxp4 leads to impeded radial migration of cortical neurons and ectopic neurogenesis from the proliferating VZ. The ectopic differentiation and deficient migration disappear when N-cadherin is over-expressed in RGCs. The data indicate that Foxp4 is essential for N-cadherin-based adherens junctions, the loss of which leads to periventricular heterotopias. We hypothesize that FOXP4 variant-associated NDDs may be caused by disruption of the adherens junctions and malformation of the cerebral cortex.

RhoGEF Trio Regulates Radial Migration of Projection Neurons via Its Distinct Domains / 神经科学通报·英文版

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.

Regulatory Mechanisms of Environmental Molecular Signaling in the Tangential Migration of Cortical Interneurons / 中国生物化学与分子生物学报

Brain activity requires the regulation of excitatory and inhibitory neurons. GABAergic interneurons are considered to prevent hyperexcitability in brain. Severe GABAergic deficits have been proved to cause pathological hyperexcitability. Most cortical interneurons originate from the ventral telencephalon and then undergo a long tangential migration to the cortex, followed by radial migration into developing cortical plate. Among them, tangential migration is considered to be the main migration manner of interneurons. The process is rather complex but also precise. With the deepening research on the tangential migration of cortical neurons, many molecules have been proved to play important roles in the process of migration. In this review, we mainly describe the migration path and migration manner of interneurons, and its underlying mechanism in two aspects. On the one hand, neurotrophins such as BDNF, NT-4, GDNF, HGF and neurotransmitters such as GABA, Glu, DA can enhance the motility of interneurons. On the other hand, several protein families as well as proteoglycans, such as Ephrin, Sema and Nrg, can bind to membrane-bound or secreted guidance cues of interneurons, providing direction clues for neuronal migration. In this review, we discussed the tangential migration of interneurons in mice, in order to provide novel insights into the regulatory molecular mechanisms of cerebral cortical development and help to develop new targets against defects in neural developments.