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

Item Type:	Article
Title:	SorCS2 regulates dopaminergic wiring and is processed into an apoptotic two-chain receptor in peripheral glia
Creators Name:	Glerup, S. and Olsen, D. and Vaegter, C.B. and Gustafsen, C. and Sjoegaard, S.S. and Hermey, G. and Kjolby, M. and Molgaard, S. and Ulrichsen, M. and Boggild, S. and Skeldal, S. and Fjorback, A.N. and Nyengaard, J.R. and Jacobsen, J. and Bender, D. and Bjarkam, C.R. and Sørensen, E.S. and Füchtbauer, E.M. and Eichele, G. and Madsen, P. and Willnow, T.E. and 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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