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 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.
authors.affiliation: The Lundbeck Foundation Research Center MIND, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark; Danish Research Institute of Translational Neuroscience DANDRITE Nordic-EMBL Partnership, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA. Electronic address: sg@biokemi.au.dk.
authors.forename: Simon
authors.initials: S
authors.lastname: Glerup
authors.affiliation: The Lundbeck Foundation Research Center MIND, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark; Danish Research Institute of Translational Neuroscience DANDRITE Nordic-EMBL Partnership, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark.
authors.forename: Ditte
authors.initials: D
authors.lastname: Olsen
authors.affiliation: The Lundbeck Foundation Research Center MIND, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark; Danish Research Institute of Translational Neuroscience DANDRITE Nordic-EMBL Partnership, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark.
authors.forename: Christian B
authors.initials: CB
authors.lastname: Vaegter
authors.affiliation: The Lundbeck Foundation Research Center MIND, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark; Danish Research Institute of Translational Neuroscience DANDRITE Nordic-EMBL Partnership, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark.
authors.forename: Camilla
authors.initials: C
authors.lastname: Gustafsen
authors.affiliation: The Lundbeck Foundation Research Center MIND, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark; Danish Research Institute of Translational Neuroscience DANDRITE Nordic-EMBL Partnership, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark.
authors.forename: Susanne S
authors.initials: SS
authors.lastname: Sjoegaard
authors.affiliation: The Lundbeck Foundation Research Center MIND, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark; Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Hermey
authors.affiliation: The Lundbeck Foundation Research Center MIND, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark; Danish Research Institute of Translational Neuroscience DANDRITE Nordic-EMBL Partnership, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark.
authors.forename: Mads
authors.initials: M
authors.lastname: Kjolby
authors.affiliation: The Lundbeck Foundation Research Center MIND, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark; Danish Research Institute of Translational Neuroscience DANDRITE Nordic-EMBL Partnership, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark; MIND Center, Stereology and Electron Microscopy Laboratory, Aarhus University, 8000 C Aarhus, Denmark.
authors.forename: Simon
authors.initials: S
authors.lastname: Molgaard
authors.affiliation: The Lundbeck Foundation Research Center MIND, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark; Danish Research Institute of Translational Neuroscience DANDRITE Nordic-EMBL Partnership, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark.
authors.forename: Maj
authors.initials: M
authors.lastname: Ulrichsen
authors.affiliation: The Lundbeck Foundation Research Center MIND, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark; Danish Research Institute of Translational Neuroscience DANDRITE Nordic-EMBL Partnership, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark.
authors.forename: Simon
authors.initials: S
authors.lastname: Boggild
authors.affiliation: The Lundbeck Foundation Research Center MIND, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark.
authors.forename: Sune
authors.initials: S
authors.lastname: Skeldal
authors.affiliation: The Lundbeck Foundation Research Center MIND, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark; Danish Research Institute of Translational Neuroscience DANDRITE Nordic-EMBL Partnership, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark.
authors.forename: Anja N
authors.initials: AN
authors.lastname: Fjorback
authors.affiliation: MIND Center, Stereology and Electron Microscopy Laboratory, Aarhus University, 8000 C Aarhus, Denmark.
authors.forename: Jens R
authors.initials: JR
authors.lastname: Nyengaard
authors.affiliation: PET Center, Aarhus University Hospital, 8000 C Aarhus, Denmark.
authors.forename: Jan
authors.initials: J
authors.lastname: Jacobsen
authors.affiliation: PET Center, Aarhus University Hospital, 8000 C Aarhus, Denmark.
authors.forename: Dirk
authors.initials: D
authors.lastname: Bender
authors.affiliation: Department of Neurosurgery, Aarhus University Hospital, 8000 C Aarhus, Denmark.
authors.forename: Carsten R
authors.initials: CR
authors.lastname: Bjarkam
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus, Denmark.
authors.forename: Esben S
authors.initials: ES
authors.lastname: Sørensen
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus, Denmark.
authors.forename: Ernst-Martin
authors.initials: EM
authors.lastname: Füchtbauer
authors.affiliation: Department of Genes and Behaviour, Max Plack Institute, 37077 Göttingen, Germany.
authors.forename: Gregor
authors.initials: G
authors.lastname: Eichele
authors.affiliation: The Lundbeck Foundation Research Center MIND, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark.
authors.forename: Peder
authors.initials: P
authors.lastname: Madsen
authors.affiliation: Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Willnow
authors.affiliation: The Lundbeck Foundation Research Center MIND, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark.
authors.forename: Claus M
authors.initials: CM
authors.lastname: Petersen
authors.affiliation: The Lundbeck Foundation Research Center MIND, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark; Danish Research Institute of Translational Neuroscience DANDRITE Nordic-EMBL Partnership, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA. Electronic address: an@biokemi.au.dk.
authors.forename: Anders
authors.initials: A
authors.lastname: Nykjaer
mesh_terms: D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000196:embryology / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003342:Corpus Striatum / Q000737:chemistry; D004298:Dopamine / Q000032:analysis / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism*; D005625:Frontal Lobe / Q000737:chemistry; D020439:Growth Cones / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009415:Nerve Net / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D012583:Schwann Cells / Q000378:metabolism*; D013378:Substantia Nigra / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D017475:Receptors, Nerve Growth Factor; C426856:SorCS2 protein, mouse; C517634:Ngfr protein, mouse; D004298:Dopamine