SorCS2 Regulates Dopaminergic Wiring and Is Processed into an Apoptotic Two-Chain Receptor in Peripheral Glia

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SorCS2 Regulates Dopaminergic Wiring and Is Processed into an Apoptotic Two-Chain Receptor in Peripheral Glia. / Glerup, Simon; Olsen, Ditte; Vægter, Christian Bjerggaard; Gustafsen, Camilla; Sjøgaard, Susanne; Hermey, Guido; Kjølby, Mads Fuglsang; Jensen, Simon Mølgaard; Ulrichsen, Maj; Hansen, Simon Bøggild; Skeldal, Sune; Fjorback, Anja Nawarecki; Nyengaard, Jens Randel; Jacobsen, Jan; Bender, Dirk; Bjarkam, Carsten R; Sørensen, Esben Skipper; Füchtbauer, Ernst-Martin; Eichele, Gregor; Madsen, Peder; Willnow, Thomas; Petersen, Claus Munck; Nykjær, Anders.

In: Neuron, Vol. 82, No. 5, 04.06.2014, p. 1074–1087.

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@article{e533374ff3a84ebabbb83ebbc5351f97,
title = "SorCS2 Regulates Dopaminergic Wiring and Is Processed into an Apoptotic Two-Chain Receptor in Peripheral Glia",
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.",
author = "Simon Glerup and Ditte Olsen and V{\ae}gter, {Christian Bjerggaard} and Camilla Gustafsen and Susanne Sj{\o}gaard and Guido Hermey and Kj{\o}lby, {Mads Fuglsang} and Jensen, {Simon M{\o}lgaard} and Maj Ulrichsen and Hansen, {Simon B{\o}ggild} and Sune Skeldal and Fjorback, {Anja Nawarecki} and Nyengaard, {Jens Randel} and Jan Jacobsen and Dirk Bender and Bjarkam, {Carsten R} and S{\o}rensen, {Esben Skipper} and Ernst-Martin F{\"u}chtbauer and Gregor Eichele and Peder Madsen and Thomas Willnow and Petersen, {Claus Munck} and Anders Nykj{\ae}r",
year = "2014",
month = "6",
day = "4",
doi = "10.1016/j.neuron.2014.04.022",
language = "English",
volume = "82",
pages = "1074–1087",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "5",

}

RIS

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

VL - 82

SP - 1074

EP - 1087

JO - Neuron

JF - Neuron

SN - 0896-6273

IS - 5

ER -