TY - JOUR
T1 - SorCS2 Regulates Dopaminergic Wiring and Is Processed into an Apoptotic Two-Chain Receptor in Peripheral Glia
AU - Glerup, Simon
AU - Olsen, Ditte
AU - Vægter, Christian Bjerggaard
AU - Gustafsen, Camilla
AU - Sjøgaard, Susanne
AU - Hermey, Guido
AU - Kjølby, Mads Fuglsang
AU - Jensen, Simon Mølgaard
AU - Ulrichsen, Maj
AU - Hansen, Simon Bøggild
AU - Skeldal, Sune
AU - Fjorback, Anja Nawarecki
AU - Nyengaard, Jens Randel
AU - Jacobsen, Jan
AU - Bender, Dirk
AU - Bjarkam, Carsten R
AU - Sørensen, Esben Skipper
AU - Füchtbauer, Ernst-Martin
AU - Eichele, Gregor
AU - Madsen, Peder
AU - Willnow, Thomas
AU - Petersen, Claus Munck
AU - Nykjær, Anders
PY - 2014/6/4
Y1 - 2014/6/4
N2 - 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.
AB - 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.
U2 - 10.1016/j.neuron.2014.04.022
DO - 10.1016/j.neuron.2014.04.022
M3 - Journal article
C2 - 24908487
SN - 0896-6273
VL - 82
SP - 1074
EP - 1087
JO - Neuron
JF - Neuron
IS - 5
ER -