Pincher-generated Nogo-A endosomes mediate growth cone collapse and retrograde signaling

Armela Joset¹, Dana A. Dodd², Simon Halegoua³, , and Martin E. Schwab¹

¹ Brain Research Institute, University of Zurich, and Department of Biology, Eidgenössische Technische Hochschule Zurich, 8057 Zurich, Switzerland
² Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390
³ Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, NY 11794

Correspondence to Armela Joset: hatkic{at}hifo.uzh.ch; or Martin E. Schwab: schwab{at}hifo.uzh.ch

Abstract: Nogo-A is one of the most potent myelin-associated inhibitors for axonal growth, regeneration, and plasticity in the adult central nervous system. The Nogo-A–specific fragment Nogo20 induces growth cone collapse, and inhibits neurite outgrowth and cell spreading by activating RhoA. Here, we show that Nogo20 is internalized into neuronal cells by a Pincher- and rac-dependent, but clathrin- and dynamin-independent, mechanism. Pincher-mediated macroendocytosis results in the formation of Nogo20-containing signalosomes that direct RhoA activation and growth cone collapse. In compartmentalized chamber cultures, Nogo20 is endocytosed into neurites and retrogradely transported to the cell bodies of dorsal root ganglion neurons, triggering RhoA activation en route and decreasing phosphorylated cAMP response element binding levels in cell bodies. Thus, Pincher-dependent macroendocytosis leads to the formation of Nogo-A signaling endosomes, which act both within growth cones and after retrograde transport in the cell body to negatively regulate the neuronal growth program.

Abbreviations: CGN, cerebellar granule neuron • CNS, central nervous system • CREB, cAMP response element binding • db-cAMP, dibutyryl cAMP • DIV, day in vitro • dn, dominant negative • DRG, dorsal root ganglion • pCREB, phosphorylated CREB • PI-PLC, phosphatidylinositol-specific phospholipase C • RBD, Rho-binding domain • wt, wild type

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