The nervous system is enormously complex, yet the number of cues that control axonal growth is surprisingly meager. Posttranslational modifications amplify diversity, but the degree to which they are employed is unclear. Here, we show that Furin and SKI-1 combine with autocatalytic cleavage and a disulfide bridge to generate four membrane-bound and three soluble forms of the repulsive guidance molecule (RGMa). We provide in vivo evidence that these proprotein convertases are involved in axonal growth and that RGMa cleavage is essential for Neogenin-mediated outgrowth inhibition. Surprisingly, despite no sequence homology, N- and C-RGMa fragments bound the same Fibronectin-like domains in Neogenin and blocked outgrowth. This represents an example in which unrelated fragments from one molecule inhibit outgrowth through a single receptor domain. RGMa is a tethered membrane-bound molecule, and proteolytic processing amplifies RGMa diversity by creating soluble versions with long-range effects as well.

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