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The ability of adult CNS neurons to successfully regenerate their axons upon injuries such as\udstroke and spinal cord injury is very limited. Over the last two decades researches have focused\udon the challenging question of how to overcome this regenerative failure. The identification of\udthe myelin associated neurite outgrowth inhibitor Nogo-A shed light on the inhibitory nature,\udcompared to the PNS, of CNS myelin. Subsequent Nogo-A neutralization experiments led to\udsuccessful CNS regeneration in animal models of spinal cord injury. The first part of Chapter 1\udsummarizes important findings regarding Nogo-A function as a neurite outgrowth inhibitor and\udgives insight into emerging roles of Nogo-A during development and disease.\udNogo-A contains two inhibitory regions for neurite outgrowth inhibition: the Nogo66 region,\udalso common to Nogo-B and Nogo-C, and the Nogo-A specific region, NogoΔ20. Whereas the\udsignaling mechanisms of the Nogo66 region are well characterized, comparatively little is known\udabout the signaling complex of NogoΔ20. Since blocking of the Nogo66 receptor complex does\udnot completely abolish myelin inhibition of neurite outgrowth, it is of great importance to\udelucidate the Nogo66 receptor independent mechanism of Nogo-A signaling.\udOver the last few years it has become clear that endocytosis plays an active role during cellular\udcommunication. A number of surface ligand-receptor complexes are known to internalize into\udcells and signal from endosomes. The second part of Chapter 1 introduces endocytosis as a\udpossible mechanism for NogoΔ20 signaling and reviews the known endocytic pathways.\udIn Chapter 2 we find that the soluble, active NogoΔ20 fragment is internalized into neuronal\udcells. The internalization into early endosomes does not follow a conventional clathrin-and\uddynamin dependent route, it rather depends on the Pincher protein and the small GTPase Rac.\udThis Pincher-mediated macroendocytosis of NogoΔ20 results in the formation of NogoΔ20\udsignalosomes that direct RhoA activation and growth cone collapse. In compartmentalized\udchamber cultures, NogoΔ20 is endocytosed into neurites and retrogradely transported to the cell\udbodies of DRG neurons, triggering RhoA activation en route and decreasing pCREB levels in\udcell bodies. The decrease of pCREB points towards an antagonistic regulation of the growth\udmachinery by Nogo-A and neurotrophins. Taken together, the findings of the present thesis\udsuggest that Pincher-dependent macroendocytosis may lead to the formation of a Nogo-A\udsignaling endosome that is retrogradely transported from the axons to the cell body thus\udsuppressing the neuronal growth program

Pincher-generated Nogo-A signalosomes mediate growth cone collapse and retrograde transport