Research ArticleNeuroscience

Neuronal Growth Cone Retraction Relies on Proneurotrophin Receptor Signaling Through Rac

Sci. Signal.  06 Dec 2011:
Vol. 4, Issue 202, pp. ra82
DOI: 10.1126/scisignal.2002060

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Promoting Neurite Retraction with ProNGF

Nerve growth factor (NGF), which was identified because of its ability to stimulate neurite outgrowth, promotes neuronal survival and differentiation during development. Like other neurotrophins, NGF is synthesized through cleavage of a precursor form and, here, Deinhardt et al. show that this precursor form (proNGF) induced the acute collapse and retraction of growth cones in cultured hippocampal neurons. ProNGF bound to a complex of the p75 neurotrophin receptor (p75NTR, which also acts as a co-receptor for NGF and other neurotrophins) and SorCS2 to stimulate neurite collapse through two distinct mechanisms. It promoted dissociation of the guanine nucleotide exchange factor Trio from the p75NTR-SorCS2 complex, decreasing activity of the Rac guanosine triphosphatase, and, in parallel, stimulated the phosphorylation and inactivation of the actin-bundling protein fascin. Thus, whereas NGF promotes neurite outgrowth, proNGF signals through a distinct pathway to elicit neurite retraction.