Neuronal growth cone retraction relies on proneurotrophin receptor signaling through rac

Abstract

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 p75NTRSorCS2
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.

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ORCID for K. Deinhardt: orcid.org/0000-0002-6473-5298

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