Objective：To explore the effects of nuclear localization sequence（NLS） and carboxyl terminus of parathyroid hormone related peptide（PTHrP） on the oligodendrocytes development and myelination in mice. Methods：PTHrP knock in（PTHrP KI）mice and their wild type（WT） littermates were accepted 5-bromo-2-deoxyuridine（BrdU） intraperitoneal injection at postnatal day 6（P6），and were sacrificed at the next day. The myelination in the central nervous system（CNS） was observed by myelin basic protein（MBP）immunohistochemical staining and electron microscope. The proliferation of oligodendrocyte progenitor cells in the hippocampus was detected by BrdU labeling and immunofluorescence staining. O4 positive oligodendrocyte progenitor cells（OPCs）from the cerebral cortex of P5 PTHrP KI mice and their WT littermates were selected and cultured in vitro. Then，the Ki67 positive cells were observed by immunofluorescence staining，the ratio of apoptotic cells was measured by flow cytometer analysis，and the proliferation and apoptosis related proteins were detected by Western blot. The differentiation ability of OPCs was inspected by 2′，3′-cyclic-nucleotide 3′-phosphodiesterase（CNPase）immunofluorescence staining after cultured in differentiation medium for 7 days. Results：Comparison to their WT littermates，PTHrP KI mice showed decreased expression of MBP positive nerve fibers and the thinner myelin sheathes of axons in the brain，decreased BrdU and oligodendrocyte transcription factor 2（Oligo2）double positive cells in hippocampus area. The in vitro cultured OPCs from PTHrP KI mice showed the decreased ratio of Ki67 positive cells，the decreased expression level of proliferation related proteins as B cell-specific MLV integration site-1（Bmi-1）and proliferating cell nuclear antigen（PCNA），the increased ratio of AV+/PI- apoptotic cells，the increased expression level of apoptotic proteins as caspase-3 and p16，and the decreased intensity of CNPase immunofluorescence after 7 days’ differentiation culture. Conclusion：Defect of NLS and C-Terminus of PTHrP leads to the decreased proliferation，increased apoptosis，and delayed differentiation of OPCs，and results in the axonal myelination disability in CNS.