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

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Item Type:	Article
Title:	SorCS2 regulates dopaminergic wiring and is processed into an apoptotic two-chain receptor in peripheral glia
Creators Name:	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. and Nykjaer, A.
Abstract:	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 p75(NTR). 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 p75(NTR)-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 p75(NTR)-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.
Source:	Neuron
ISSN:	0896-6273
Publisher:	Cell Press
Volume:	82
Number:	5
Page Range:	1074-87
Date:	4 June 2014
Official Publication:	https://doi.org/10.1016/j.neuron.2014.04.022
PubMed:	View item in PubMed

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