The non-apoptotic role of p53 in neuronal biology: enlightening the dark side of the moon

The transcription factor p53 protects neurons from transformation and DNA damage through the induction of cell‐cycle arrest, DNA repair and apoptosis in a range of in vitro and in vivo conditions. Indeed, p53 has a crucial role in eliciting neuronal cell death during development and in adult organisms after exposure to a range of stressors and/or DNA damage. Nevertheless, accumulating evidence challenges this one‐sided view of the role of p53 in the nervous system. Here, we discuss how—unexpectedly—p53 can regulate the proliferation and differentiation of neural progenitor cells independently of its role in apoptosis, and p53 post‐translational modifications might promote neuronal maturation, as well as axon outgrowth and regeneration, following neuronal injury. We hope to encourage a more comprehensive view of the non‐apoptotic functions of p53 during neural development, and to warn against oversimplifications regarding its role in neurons. In addition, we discuss how further insight into the p53‐dependent modulation of these mechanisms is necessary to elucidate the decision‐making processes between neuronal cell death and differentiation during development, and between neuronal degeneration and axonal regeneration after injury.