MytlL Promotes The Differentiation Of Oligodendrocyte Precursor Cells And Remyelination

Myelin is a membrane structure wrapping around the axons,which mainly plays roles in the maintance of neurological functions and axonal insulation,accelerating nervous signal transmission and axonal protection.Myelin damage will lead to irreversible axonal injury,a serious impact on cognitive or motor function.Oligodendrocytes,the myelin-forming cells for axon ensheathment in the central nervous system,are critical for maintaining the conduction velocity of nerve impulses and proper brain function.Oligodendrocyte precursor cells(OPCs)originate in specific areas of the central nervous system(CNS).Once generated,they migrate to their destinations where they differentiate into mature oligodendrocytes.OPCs react to damage in demyelinating diseases,like multiple sclerosis(MS),representing a key element in spontaneous remyelination.The differentiation and maturation of Oligodendrocyte precursor cells(OPCs)is a prerequisite for myelination and remyelination in CNS.The failure of OPCs to achieve terminal differentiation often contributes to the unsuccessful remyelination in a variety of human demyelinating diseases.OPCs,which are abundant throughout the adult CNS,respond to demyelinating injury by first undergoing activation,colonization of the demyelinated area by proliferation and migration,and eventually differentiation into new myelin-forming oligodendrocytes.Critical to this process is the switch from a proliferative/migratory state to the exiting from the cell cycle and differentiation into a nondividing,nonmigratory mature oligodendrocyte.In both developmental myelination and remyelination,the OPC is guided through these mutually exclusive phases of proliferation and differentiation by a complex network of transcription factors.Oligodendrocyte development involves a complex interplay of a variety of intrinsic,extrinsic and epigenetic factors that are implicated in OPC cycle exit and differentiation.Thus,transcriptional regulation via synchronized expression of transcription factors,posttranscriptional control by microRNAs and epigenetic regulation have been identified as major mechanisms that direct differentiation of OPCs into myelinating oligodendrocytes.During embryogenesis,the initial specification of neural stem cells into OPCs requires expression of the transcription factor Olig2.After OPC specification and migration,the efficient generation of myelinating oligodendrocytes depends on expression of other transcription factors,including Nkx2.2,Olig1,Sox10,and YY1.However,the molecular mechanisms controlling OPCs differentiation under pathological conditions remain largely unknown.Myt1L(myelin transcription factor 1-like)is a protein structurally similar to myelin transcription factor 1.It was reported to be expressed mainly in neurons.Deletion of Myt1 L in chromosome band 2p25.3 or mutations of Myt1 L gene are associated with mental retardation,schizophrenia or depression.The aim of the present study was to evaluate the roles of Myt1 L on OPCs differentiation.We found that Myt1 L was expressed in NG2+ and CC1+ oligodendrocyte linage cells during myelination and remyelination.The expression level of Myt1 L in NG2+ cells was significantly higher than that in CC1+ oligodendrocyte linage cells.In primary cultured OPCs,overexpression of Myt1 L promoted OPCs differentiation,while knockdown of Myt1 L inhibit OPCs differentiation.Moreover,genetic inactivation of Myt1 L caused defects in CNS remyelination following injury.Mechanically,Myt1 L bound to the promoters of Olig1 and transcriptionally controlled Olig1 expression.Taken together,our findings suggest that Myt1 L is an essential regulator of OPCs differentiation,thereby supporting Myt1 L to be a potential therapeutic target for the treatment of demyelinating disease.