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Journal Article

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;

Fulltext (public)

2157444.pdf
(Publisher version), 9MB

Supplementary Material (public)

2157444-Suppl-1.pdf
(Supplementary material), 47MB

Citation

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.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0027-792B-3
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 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.