SorCS2 regulates dopaminergic wiring and is processed into an apoptotic 
two-chain receptor in peripheral glia.

Glerup, S.; Olsen, D.; Vaegter, C. B.; Gustafsen, C.; Sjoegaard, S. S.; Hermey, G.; Kjolby, M.; Molgaard, S.; Ulrichsen, M.; Boggild, S.; Skeldal, S.; Fjorback, A. N.; Nyengaard, J. R.; Jacobsen, J.; Bender, D.; Bjarkam, C. R.; Sørensen, E. S.; Füchtbauer, E. M.; Eichele, G.; Madsen, P.; Willnow, T. E.; Petersen, C. M.; Nykjaer, A.

doi:10.1016/j.neuron.2014.04.022

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SorCS2 regulates dopaminergic wiring and is processed into an apoptotic two-chain receptor in peripheral glia.

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Eichele, G.
Department of Genes and Behavior, MPI for biophysical chemistry, Max Planck Society;

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http://www.sciencedirect.com/science/article/pii/S0896627314003377
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Zitation

Glerup, S., Olsen, D., Vaegter, C. B., Gustafsen, C., Sjoegaard, S. S., Hermey, G., et al. (2014). SorCS2 regulates dopaminergic wiring and is processed into an apoptotic two-chain receptor in peripheral glia. Neuron, 82(5), 1074-1087. doi:10.1016/j.neuron.2014.04.022.

Zitierlink: https://hdl.handle.net/11858/00-001M-0000-0027-792B-3

Zusammenfassung

Balancing 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.