RESUMEN
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.
Asunto(s)
Apoptosis , Encéfalo/metabolismo , Neuronas Dopaminérgicas/metabolismo , Red Nerviosa/metabolismo , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/metabolismo , Receptores de Superficie Celular/química , Receptores de Superficie Celular/metabolismo , Células de Schwann/metabolismo , Animales , Encéfalo/embriología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Cuerpo Estriado/química , Dopamina/análisis , Dopamina/metabolismo , Lóbulo Frontal/química , Conos de Crecimiento/metabolismo , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas/metabolismo , Receptores de Factor de Crecimiento Nervioso/metabolismo , Sustancia Negra/metabolismo , Área Tegmental Ventral/metabolismoRESUMEN
Neurotrophins are essential for development and maintenance of the vertebrate nervous system. Paradoxically, although mature neurotrophins promote neuronal survival by binding to tropomyosin receptor kinases and p75 neurotrophin receptor (p75(NTR)), pro-neurotrophins induce apoptosis in cultured neurons by engaging sortilin and p75(NTR) in a death-signaling receptor complex. Substantial amounts of neurotrophins are secreted in pro-form in vivo, yet their physiological significance remains unclear. We generated a sortilin-deficient mouse to examine the contribution of the p75(NTR)/sortilin receptor complex to neuronal viability. In the developing retina, Sortilin 1 (Sort1)(-/-) mice showed reduced neuronal apoptosis that was indistinguishable from that observed in p75(NTR)-deficient (Ngfr(-/-)) mice. To our surprise, although sortilin deficiency did not affect developmentally regulated apoptosis of sympathetic neurons, it did prevent their age-dependent degeneration. Furthermore, in an injury protocol, lesioned corticospinal neurons in Sort1(-/-) mice were protected from death. Thus, the sortilin pathway has distinct roles in pro-neurotrophin-induced apoptotic signaling in pathological conditions, but also in specific stages of neuronal development and aging.
