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

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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.