SorCS2 regulates dopaminergic wiring and is processed into an apoptotic two-chain receptor in peripheral glia

Neuron. 2014 Jun 4;82(5):1074-87. doi: 10.1016/j.neuron.2014.04.022.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Brain / embryology
  • Brain / metabolism*
  • Brain-Derived Neurotrophic Factor / metabolism
  • Corpus Striatum / chemistry
  • Dopamine / analysis
  • Dopamine / metabolism
  • Dopaminergic Neurons / metabolism*
  • Frontal Lobe / chemistry
  • Growth Cones / metabolism
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nerve Net / metabolism*
  • Nerve Tissue Proteins / chemistry*
  • Nerve Tissue Proteins / metabolism*
  • Neurons / metabolism
  • Receptors, Cell Surface / chemistry*
  • Receptors, Cell Surface / metabolism*
  • Receptors, Nerve Growth Factor / metabolism
  • Schwann Cells / metabolism*
  • Substantia Nigra / metabolism
  • Ventral Tegmental Area / metabolism

Substances

  • Brain-Derived Neurotrophic Factor
  • Nerve Tissue Proteins
  • Receptors, Cell Surface
  • Receptors, Nerve Growth Factor
  • SorCS2 protein, mouse
  • Ngfr protein, mouse
  • Dopamine