Parathyroid hormone‐related peptide (PTHrP) acts under physiological conditions to regulate normal development of several tissues and organs. The role of PTHrP in spinal cord development has not been characterized. Pthrp knock in (Pthrp KI) mice were genetically modified to produce PTHrP in which there is a deficiency of the nuclear localization sequence (NLS) and C‐terminus. Using this genetically modified mouse model, we have characterized its effect on spinal cord development early postnatally. The spinal cords from Pthrp KI mice displayed a significant reduction in its length, weight, and cross‐sectional area compared to wild‐type controls. Histologically, there was a decreased development of neurons and glial cells that caused decreased cell proliferation and increased apoptosis. The neural stem cells (NSCs) cultures also revealed decreased cell proliferation and differentiation and increased apoptosis. The proposed mechanism of delayed spinal cord development in Pthrp KI mice may be due to alteration in associated pathways in regulation of cell‐division cycles and apoptosis. There was significant downregulation of Bmi‐1 and upregulation of cyclin‐dependent kinase inhibitors p27, p21, and p16 in Pthrp KI animals. We conclude that NLS and C‐terminus peptide segments of PTHrP play an important role in inhibiting cell apoptosis and stimulation of cellular proliferation necessary for normal spinal cord development.

中文翻译：

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PTHrP 核定位和羧基末端序列在出生后脊髓发育中的作用

甲状旁腺激素相关肽 (PTHrP) 在生理条件下发挥作用，调节多种组织和器官的正常发育。PTHrP 在脊髓发育中的作用尚未确定。Pthrp敲入 ( Pthrp KI) 小鼠经过基因改造以产生 PTHrP，其中缺乏核定位序列 (NLS) 和 C 端。使用这种转基因小鼠模型，我们已经描述了它对出生后早期脊髓发育的影响。来自Pthrp的脊髓与野生型对照相比，KI 小鼠的长度、重量和横截面积显着减少。组织学上，神经元和神经胶质细胞发育减少，导致细胞增殖减少和细胞凋亡增加。神经干细胞 (NSCs) 培养物还显示细胞增殖和分化减少，细胞凋亡增加。Pthrp KI 小鼠脊髓发育延迟的机制可能是由于调节细胞分裂周期和细胞凋亡的相关途径的改变。Pthrp 中 Bmi-1 显着下调，细胞周期蛋白依赖性激酶抑制剂 p27、p21 和 p16上调KI动物。我们得出结论，PTHrP 的 NLS 和 C 末端肽段在抑制细胞凋亡和刺激正常脊髓发育所必需的细胞增殖中起重要作用。