SorCS2 Regulates Dopaminergic Wiring and Is Processed into an Apoptotic Two-Chain Receptor in Peripheral Glia

•SorCS2 is a single-chain receptor in CNS neurons but is cleaved into a two-chain variant in PNS glia•Single-chain SorCS2 is required for growth cone collapse in CNS neurons•Two-chain SorCS2 is critical for Schwann cell apoptosis following peripheral injury•SorCS2 knockouts display dopaminergic hyperinnervation and an ADHD-like behavior

SummaryBalancing trophic and apoptotic cues is critical for development and regeneration of neuronal circuits. Here we identify SorCS2 as a proneurotrophin (proNT) receptor, mediating both trophic and apoptotic signals in conjunction with p75NTR. CNS neurons, but not glia, express SorCS2 as a single-chain protein that is essential for proBDNF-induced growth cone collapse in developing dopaminergic processes. SorCS2- or p75NTR-deficient in mice caused reduced dopamine levels and metabolism and dopaminergic hyperinnervation of the frontal cortex. Accordingly, both knockout models displayed a paradoxical behavioral response to amphetamine reminiscent of ADHD. Contrary, in PNS glia, but not in neurons, proteolytic processing produced a two-chain SorCS2 isoform that mediated proNT-dependent Schwann cell apoptosis. Sciatic nerve injury triggered generation of two-chain SorCS2 in p75NTR-positive dying Schwann cells, with apoptosis being profoundly attenuated in Sorcs2−/− mice. In conclusion, we have demonstrated that two-chain processing of SorCS2 enables neurons and glia to respond differently to proneurotrophins.