The Role Of Kif2a In Embryonic Neocortical Neurogenesis And Neogenin In Adult Hippocampal Neurogenesis

During the embryonic brain development,the neurogenesis of forebrain cortex is from neuroepithelial ventricular zone(VZ).Neural stem cells(NSCs)in the VZ first proliferate and undergo self-renewal to expand NSCs pool.Subsequently,they migrate into the subventricular zone(SVZ)and switch to intermediate progenitor cells(IPCs).Finally,differentiated new born neurons from NSCs reach the cortical plate(CP)through radial migration,and then build functional six layers structure.As reported,disruption ofembryonic neurogenesis leads to many cortical malfunctions,such asmental retardation and tuberous sclerosis.To date,embryonic cortical neurogenesis has long been hot topics in the related nervous system developmental research area.Thus,it is of considerable interest and significance to explore the molecular mechannisms for neurological disease and treatment during embryonic cortical neurogenesis.Kinesin family member 2a(Kif2a),a member of the Kinesin-13 family,which is different from traditional Kinesin proteins,not involved in intracellular transport.Kif2 a is first identified as a kinesin motor protein that binds at the plus end of microtubules(MTs),and depolymerizes MTs depending on the activity of adenosine triphosphate(ATP).In this study,we found that Kif2 a plays an important role in neocortical neurogenesis.Knocking down Kif2 a in NSCs/NPCs inhibited their proliferation and promoted neuronal differentiation in both mouse embryos and in vitro cultured NSCs/NPCs.Further analysis shows that Kif2 a regulates the level of β-catenin through PI3K-AKT-GSK3βsignaling pathway,which provides a theoretical fundament for exploring the molecular mechanisms during cortical neurogenesis.During the adult mice brain development,there are two neurogenic regions retaining the ability to generate new neurons.The subventricular zone(SVZ)of the lateral ventricular and the subgranular zone(SGZ)of hippocampal dentate gyrus(DG).In the SVZ,neuroblasts migrate into olfactory bulb(OB)through the rostral migratory stream(RMS)and then differentiate into interneurons.In the SGZ,neural stem cells(NSCs)give rise to new-born neurons,which undergo several developmental stages and finally become local excitatory granule neurons and establish synaptic connection.Normal hippocampal neurogenesis is essential for the functions of nervous system,under physiological conditions,impaired hippocampal neurogenesis results in many neurological diseases,such as learning and memory disorders and depression.Thus,research on adult hippocampal neurogenesis will contributes to understand well of the development of nervous system,and gives new insights into the treatment of neurological diseases.Neogenin,a member of transmembrane receptors and homologue of deleted in colorectal cancer(DCC),binds to netrins,repulsive guidance molecules(RGMs)and bone morphogenetic proteins(BMPs)ligands to regulate multiple functions including axon guidance,neural tube formation,neuronal survival and tumorigenesis.In this study,we first analyzed the expression pattern of neogenin in hippocampus,and neogenin was shown to be strongly expressed in NSCs and immature neurons.We then used conditional knockout mice to selectively knock out neogenin in NSCs,we found that neogenin depletion significantly inhibited the proliferation of NSCs by decreasing Gli1 level.In differentiation stage,loss of neogenin promoted more NSCs differentiated into astrocytes,but no effect on neuronal differentiation.During dendritic development,knockout neogenin in immature neurons significantly reduced their total dendritic length,branch numbers and dendritic complexity.In addition,electrophysiological recording also showed that the frequency of mEPSC was markedly decreased,but little effect on mIPSC.In behavior test,compared to control group,mice with depletion of neogenin in NSCs/NPCs preferred to show depressive-like behaviors.Taken together,we demonstrated new factors to regulate embryonic cortical neurogenesis and adult hippocampal neurogenesis.Kif2 a plays a critical role in promoting cortical NSCs/NPCs proliferation or self-renewal but suppresses neuronal differentiation at E13.5.During adult hippocampal neurogenesis,neogenin promotes the proliferation of NSCs by Gli1,and inhibits their astrocytic differentiation,meanwhile promotes dendriticdevelopment and prevents depression.