COPⅡ Mediates Autocrine PTN To Regulate Oligodendrocyte Development And Conditional Knockout Of Nucleoporin Sehl Impairs Neurogenesis

During mice development,cells undergo frequently cargo transport.COPⅡ vesicle is an important mediator in cargo transport from the endoplasmic reticulum to the Golgi apparatus.Here we found that COPⅡ components were expressed in oligodendrocytes.Knockdown of COPⅡ components or inhibition of COPⅡ vesicle transport impaired oligodendrocyte precursor cell(OPC)development.Conditional knock out of Sec13,a COPⅡ component,resulted in defective OPC differentiation and myelination in vivo and in vitro,and OPC remained undifferentiated.The COPⅡ components Sec 13 and Sec31a were upregulated after myelin sheath injury,while overexpression of Sec 13 and Sec31a could promote OPC differentiation.Further studies showed that Sec 13 deletion resulted in reduction of OPC secretion.OPC autocrine factors contribute to selfdifferentiation.Among the secreted factors,autocrine factor PTN could not be secreted and is stacked after loss of COPⅡ components.PTN could bind to the OPC membrane receptor PTPRZ1,thereby inhibiting PTPRZ1 dephosphorylation.PTN regulates the differentiation of OPC through the PTN-PTPRZ1-p190RhoGAP signaling pathway.In summary,this study found that autocrine PTN mediated by COPⅡ vesicle plays an important role in OPC differentiation and CNS myelination.The nuclear pore complex mediates nucleocytoplasmic exchanges of cargos required for transcription、translation and many other cellular processes and is related to many neurodevelopmental diseases.In this article,conditional knockout mice models were firstly used to study the role of nucleoporins during the development of neural stem cell(NSC).We found that nucleoporin Sehl was expressed during NSC differentiation.The Seh1cKO NSCs were unable to proliferate and differentiate normally,leading to defficient neurogenesis and cerebral cortex malformation.Sehl deletion in adult mice also resulted in a decrease in neurogenesis.Although it did not impair the distribution and localization of nuclear pore complexes under proliferation conditions,knockout of Sehl caused a delay in cell-cycle progression.NSC was stucked in the pre-mitotic phase.There was a reduction of cells passing through the cell cycle.Under differentiation conditions,the absence of Sehl caused decreased terminal differentiation of NSCs and a decline in the ability to form neurons.It probably activated the P53-dependent apoptotic pathway at the same time.Together,we generated conditional knockout mice models to study the roles of COPII in vesicle transport and nucleoporins in nucleocytoplasmic transport during neurodevelopment.Our stdudy might serve as a basis for future studies of myelin development,neurodevelopment and the treatment of clinical developmental diseases.Besides,we identify an autocrine growth factor PTN,which promotes myelination.It provides a new way for the prevention and treatment of demyelination diseases.