Growth Cones Need p53

Science Signaling  28 Apr 2009:
Vol. 2, Issue 68, pp. ec150
DOI: 10.1126/scisignal.268ec150

The tumor suppressor p53 is best known for its functions as a transcription factor, and in this context it is known to contribute to neurite outgrowth by inducing the expression of genes encoding proteins important for the regulation of actin and various guidance molecules. Qin et al. show that a specifically phosphorylated form of p53 also appears to function in the growth cone. The p53 protein is posttranslationally modified in several ways, and immunofluorescence analysis of primary cultures of mouse neurons indicated that p53 phosphorylated on Ser15 (p-p53) was abundant in axons and growth cones but not in dendrites, whereas acetylated p53 was present in the axon but not the growth cone or dendrites. This pattern was present through 5 days in vitro (DIV), and by DIV10 p-p53 was mostly found in the cell body. Multiple conformations of p53 also contribute to the complexity of p53 function. Labeling of primary neuron cultures with antibodies specific for the “wild-type” conformation, which can function as a transcription factor, and a “mutant” conformation, which is restricted to the cytoplasm and does not function as a transcription factor, showed very little p53 in the wild-type conformation and showed that the mutant conformation was abundant both in the cell body and processes. In cultured hippocampal neurons, overexpression of p53 promoted expansion of the growth cone area, whereas suppression of p53 with pifithrin-α (inhibitor of transcriptional and nontranscriptional activity of p53) or with pifithrin-μ (selective inhibitor of nontranscriptional activity of p53) or with silencing RNA (siRNA) triggered growth cone collapse. Growth cone collapse triggered by pifithrin-α or pifithrin-μ was prevented by application of an inhibitor of the Rho kinase ROCK, suggesting that p53 may negatively regulate ROCK activity in the growth cone.

Q. Qin, M. Baudry, G. Liao, A. Noniyev, J. Galeano, X. Bi, A novel function for p53: Regulation of growth cone motility through interaction with Rho kinase. J. Neurosci. 29, 5183–5192 (2009). [Abstract] [Full Text]