The regulation of the transcription factor p53 in neurite outgrowth and neuron differentiation

P53抑癌基因是一种DNA结合、序列特异的转录因子，可以激活大量调控细胞生长、存活和分化的基因的表达。P53的水平和活性受翻译后变化的调节，包括磷酸化和乙酰化。在神经系统中，P53可以促进神经元的凋亡，也可以促进细胞分化。重要的是，在损伤后轴突再生的过程中，神经元分化的机制被重述。因此，阐明神经元分化的分子机制可以为轴突再生的调控提供新的思路。我们最近观察到P53的转录活性是神经元分化和轴突再生所必需的。P53如何将其转录活性从促凋亡功能转变为促神经元分化和轴突可塑性功能仍不清楚。我假设P53的促神经元分化活性受特定的翻译后修饰调控，该修饰由生长因子触发，将其转录活性重新定向到促分化启动子。为了验证这一假说，我提出了以下目标：1)研究P53翻译后修饰和信号通路在轴突生长和神经元分化中的作用；2)评估特定的P53翻译后修饰在神经系统发育过程中在神经元中的表达。这项研究有助于了解神经系统的发育障碍，并为增强脊髓和脑损伤等疾病以及阿尔茨海默氏症和帕金森氏病等神经退行性疾病的神经可塑性和再生提供新的药理靶点。

The p53 tumor suppressor gene functions as a DNA-binding, sequence-specific transcription factor that activates the expression of a plethora of genes which regulate cellular growth, survival and differentiation. P53 levels and activity are regulated by post-translational changes, including phosphorylation and acetylation. In the nervous system, p53 can promote neuronal apoptosis, but also cell differentiation. Importantly, mechanisms of neuron differentiation are recapitulated during axon regeneration after injury. Therefore, clarification of the molecular mechanisms of neuron differentiation can provide insights into the regulation of axon regeneration. We have recently observed that p53 transcriptional activity is required for neuronal differentiation and axon regeneration. How p53 switches its transcriptional activity form a pro-apoptotic to a pro-neuronal differentiation and axonal plasticity function is still obscure. I hypothesize that the pro-neuronal differentiation activity of p53 is regulated by specific post-translational modifications, triggered by growth factors, which re-direct its transcriptional activity to pro-differentiation promoters. To test this hypothesis I propose the following aims: 1) to investigate the role of p53 post-translational modifications and signaling pathways in neurite outgrowth and neuronal differentiation; 2) to evaluate the in vivo expression of specific p53 post-translational modifications in neurons during development of the nervous system. This studies could contribute to the understanding of developmental disorders of the nervous system, and provide new pharmacological targets to enhance nerve plasticity and regeneration in disorders like spinal cord and brain injury, and in neurodegenerative disease such as Alzheimer's and Parkinson's disease.