p53 Regulates the Neuronal Intrinsic and Extrinsic Responses Affecting the Recovery of Motor Function following Spinal Cord Injury
p53 Regulates the Neuronal Intrinsic and Extrinsic Responses Affecting the Recovery of Motor Function following Spinal Cord Injury
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DOI：
10.1523/jneurosci.1925-12.2012
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发表时间：
2012-10-03
影响因子：
5.3
通讯作者：
Di Giovanni, Simone
中科院分区：
文献类型：
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作者：
Floriddia, Elisa M.;Rathore, Khizr I.;Di Giovanni, Simone
脊髓创伤后，有限的生理轴突发芽，有助于部分恢复的功能是依赖于神经元的内在特性，以及抑制性胶质细胞环境。转录因子p53参与DNA修复、细胞周期、细胞存活和轴突生长，表明p53是影响脊髓损伤后功能恢复的轴突和神经胶质反应的关键修饰剂。事实上，在脊髓背侧半切损伤模型中，我们观察到与野生型小鼠相比，p53（-/-）小鼠的运动恢复明显受损。p53（-/-）脊髓显示活化的小胶质细胞/巨噬细胞的数量增加，并且在损伤部位有较大的瘢痕。功能丧失和获得实验表明p53作为小胶质细胞/巨噬细胞增殖的直接调节剂。在轴突水平，p53（-/-）小鼠表现出更明显的死亡的皮质脊髓束（CST）和CST和脊髓胆碱能纤维的发芽能力下降。在p53（-/-）小鼠中，感觉运动皮层中p53的体内表达挽救并增强了CST的发芽潜力，而同样地，p53（-/-）培养的皮层神经元中p53的表达挽救了轴突生长的缺陷，这表明p53在调节CNS神经元内在发芽能力中的直接作用。总之，我们表明，p53在影响脊髓损伤后运动功能恢复的外在和内在水平上起着重要的调节作用。因此，我们建议p53作为一个新的潜在的多层次治疗脊髓损伤的目标。
Following spinal trauma, the limited physiological axonal sprouting that contributes to partial recovery of function is dependent upon the intrinsic properties of neurons as well as the inhibitory glial environment. The transcription factor p53 is involved in DNA repair, cell cycle, cell survival, and axonal outgrowth, suggesting p53 as key modifier of axonal and glial responses influencing functional recovery following spinal injury. Indeed, in a spinal cord dorsal hemisection injury model, we observed a significant impairment in locomotor recovery in p53(-/-) versus wild-type mice. p53(-/-) spinal cords showed an increased number of activated microglia/macrophages and a larger scar at the lesion site. Loss-and gain-of-function experiments suggested p53 as a direct regulator of microglia/macrophages proliferation. At the axonal level, p53(-/-) mice showed a more pronounced dieback of the corticospinal tract (CST) and a decreased sprouting capacity of both CST and spinal serotoninergic fibers. In vivo expression of p53 in the sensorimotor cortex rescued and enhanced the sprouting potential of the CST in p53(-/-) mice, while, similarly, p53 expression in p53(-/-) cultured cortical neurons rescued a defect in neurite outgrowth, suggesting a direct role for p53 in regulating the intrinsic sprouting ability of CNS neurons. In conclusion, we show that p53 plays an important regulatory role at both extrinsic and intrinsic levels affecting the recovery of motor function following spinal cord injury. Therefore, we propose p53 as a novel potential multilevel therapeutic target for spinal cord injury.