Insufficient And Excessive Glucocorticoid Receptor-mediated Signal Transduction Affects Neuronal Migration

The development of cerebral cortex undergoes the proliferation and polarization of neural precursor cells,and the normal migration and accurate localization of neurons after mitosis.The migration and localization of newborn neurons in time and space are crucial to the normal development of the brain.Studies have shown that disorders occurring during brain development can lead to autism,depression,schizophrenia and a series of related neurological diseases.Therefore,it is of great significance to study the physiological process and related mechanism of brain development for us to solve related diseases in clinical practice.Glucocorticoids(GCs)are a kind of steroid hormones that regulate a variety of physiological activities of human body.Clinically,glucocorticoids play anti-inflammatory and immunosuppressive roles by combining with Glucocorticoid receptors(GRs).New evidence also suggests that inappropriate levels of GC and GR impair brain development and lead to severe neurological disorders.Clinical and epidemiological studies have shown that maternal exposure to various adverse environmental stresses during the fetal period can lead to increased GC levels in the fetus,while excessive and premature GC exposure can change the expression of some key genes in the brain and increase the risk of adult depression,anxiety and other mental system diseases.For example,elevated maternal GC induced by maternal stress alters the brain structure of the fetus,leading to attention and learning disabilities in adulthood,and prenatal GC exposure reduces cortical gesticulation index and leads to a decrease in cortical surface area in infants.In addition,reduced GR expression is associated with schizophrenia,and studies in mouse models have also demonstrated that abnormal GR expression significantly affects neurogenesis,synaptic plasticity,and behavioral responses.However,the role of GC/GR signaling in early brain development is not fully understood.In this study,we found that a stable level of GR expression is essential for brain development.Electroporation experiments in utero during embryo demonstrated that both GR knockdown and overexpression severely impair neuronal migration.Further studies have shown that GR gene knockdown leads to multipolar-bipolar conversion of neurons,impairs normal migration and final localization of neurons,while GR overexpression mainly blocks the development of migratory neuron-guided processes,thus affecting transient migration of neurons.In order to elucidate the underlying mechanism,we screened the protein levels of downstream molecules and identified the Subfamily member A of the small G protein superfamily(Rho A)as the factor negatively regulated by GR.The restoration of Rho A protein level partially saved the migration defects of GR gene knockdown and GR overexpression neurons,suggesting that Rho A plays a major role in GR-mediated migration of neurons.These data suggest that appropriate levels of GC/GR signaling are essential for precise control of neuron migration.