The major function of oligodendrocytes(OLs)is the formation of myelin sheaths in the CNS.Oligodendrocytes develop from oligodendrocytes precursor cells(OPCs)and failure of OPC maturation and myelination leads to permanent axonal damage and irreversible functional loss in diseases such as multiple sclerosis(MS).The control of differentiation of OPCs into OLs is dependent on multiple cues.However,how precisely OPC differentiation,myelination and remyelination are regulated is still poorly understand.Cyclin dependent kinase 5(Cdk5)plays critical roles in the regulation of neuronal migration,differentiation and axon outgrowth.Here we report a novel role of Cdk5 as an integrated mediator in regulating OL development,myelination and myelin repair.We show lack of Cdk5 in OLs compromised OPC maturation and myelination.In conditional CNP-Cre;Cdk5fl/fl knockout mice(Cdk5 CKO),MBP and PLP expression were significant reduced in the spinal cords,with no change in OPC proliferation suggesting Cdk5 is critical for the transition of OPCs into mature OLs.Further,we demonstrated that Cdk5 is important for adult OL maturation and remyelination.In the Cdk5 CKO,myelin repair was delayed significantly in response to focal LPC demyelinating lesions compared to WT animals.The lack of myelin repair was reflected in decreased expression of MBP and PLP and a reduction of myelinated axons in the lesion.The number of CC1+ cells in the lesion sites was significantly reduced in Cdk5 CKO compared to WT animals although the total number of OPCs(Olig2+ cells)was slightly increased suggesting Cdk5 loss perturbs the transition of early OL lineage cell into mature OL and subsequent remyelination.The failure of remyelination in Cdk5 CKO animals was associated with a reduction in signaling through the Akt pathway and an enhancement of Gsk-3β signaling pathways.Together,these data suggest that Cdk5 is critical in regulating the transition of adult OPCs to mature OLs and that it is essential for myelin repair in adult CNS.