Neuronal Growth Cone Retraction Relies Upon Proneurotrophin Receptor Signaling Through Rac

Growth of axons and dendrites is a dynamic process that involves guidance molecules, adhesion proteins, and neurotrophic factors. Although neurite extension during development has been extensively studied, the intracellular mechanisms that mediate neurite retraction are poorly understood. Here, we show that the proneurotrophin, proNGF, induces acute collapse of growth cones of cultured hippocampal neurons. This retraction is initiated by an interaction between p75NTR and the sortilin family member, SorCS2 (sortilin-related VPS10 domain containing receptor 2). Binding of proNGF to the p75NTR-SorCS2 complex induced growth cone retraction by initiating the dissociation of the guanine-nucleotide exchange factor Trio from the p75NTR- SorCS2 complex, resulting in decreased Rac activity, and consequently, growth cone collapse. The actin-bundling protein fascin also became inactivated, contributing to the destabilization and collapse of actin filaments. These results identify a bifunctional signaling mechanism by which proNGF regulates actin dynamics to modulate neuronal morphology acutely