Exosomes promote axon outgrowth by engaging the Wnt-Planar Cell Polarity pathway

Abstract

In neurons, the acquisition of a polarized morphology is achieved upon the outgrowth of a single axon from one of several neurites. Exosomes from diverse sources are known to promote the neurite outgrowth, however, the role of fibroblast-derived exosomes on axon elongation in neurons of the central nervous system under growth permissive conditions remains unclear. Here, we show that fibroblast-derived exosomes promote axon outgrowth and a polarized neuronal morphology in mouse primary embryonic cortical neurons. Mechanistically, we demonstrate that the exosome-induced increase in axon outgrowth requires endogenous Wnts and core PCP components including Prickle, Vangl, Frizzled and Dishevelled. We demonstrate that exosomes are internalized by neurons, colocalize with Wnt7b and induce relocalization of Vangl2 to the distal axon during axon outgrowth. In contrast, exosomes derived from neurons or astrocytes do not promote axon outgrowth, while exosomes from activated astrocytes inhibit elongation. Thus, our data reveals that fibroblast-derived exosomes promote axon elongation through the Wnt-PCP pathway in a manner that is dependent on endogenous Wnts.