| Literature DB >> 24908487 |
Simon Glerup1, Ditte Olsen2, Christian B Vaegter2, Camilla Gustafsen2, Susanne S Sjoegaard2, Guido Hermey3, Mads Kjolby2, Simon Molgaard4, Maj Ulrichsen2, Simon Boggild2, Sune Skeldal5, Anja N Fjorback2, Jens R Nyengaard6, Jan Jacobsen7, Dirk Bender7, Carsten R Bjarkam8, Esben S Sørensen9, Ernst-Martin Füchtbauer9, Gregor Eichele10, Peder Madsen5, Thomas E Willnow11, Claus M Petersen5, Anders Nykjaer12.
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.Entities:
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Year: 2014 PMID： 24908487 DOI： 10.1016/j.neuron.2014.04.022
Source DB: PubMed Journal: Neuron ISSN： 0896-6273 Impact factor: 17.173