Sema3F downregulates p53 expression leading to axonal growth cone collapse in primary hippocampal neurons

Hippocampal nerve growth is regulated by the coordinated action of numerous external stimuli, including positively acting neurotrophin-derived growth cues and restrictive semaphorin cues, however the underlying cellular mechanisms remain largely unclear. We examined the potential cellular mechanism of Semaphorin3F (Sema3F) in cultured primary hippocampal neurons. We show that Sema3F can down-regulate p53 expression in primary hippocampal neurons, thereby contributing to growth cone collapse. Sema3F suppressed p53-induced pathways, which we show to be required to maintain growth cone structure. Sema3F-induced growth cone collapse was partially reversed by overexpression of p53, which promoted growth cone extension. Inhibition of p53 function by inhibitor, siRNAs, induced axonal growth cone collapse, whereas p53 over-expression led to larger growth cones in cultured primary hippocampal neurons.These data reveal a novel mechanism by which Sema3F can induce hippocampal neuron growth cone collapse and provide evidence for an intracellular mechanism for cross talk between positive and negative axon growth cues.