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Roles for the pro-neurotrophin receptor sortilin in neuronal development, aging and brain injury

Official URL:https://doi.org/10.1038/nn2000
PubMed:View item in PubMed
Creators Name:Jansen, P. and Giehl, K. and Nyengaard, J.R. and Teng, K. and Lioubinski, O. and Sjoegaard, S.S. and Breiderhoff, T. and Gotthardt, M. and Lin, F. and Eilers, A. and Petersen, C.M. and Lewin, G.R. and Hempstead, B.L. and Willnow, T.E. and Nykjaer, A.
Journal Title:Nature Neuroscience
Journal Abbreviation:Nat Neurosci
Volume:10
Number:11
Page Range:1449-1457
Date:November 2007
Keywords:Apoptosis, Brain Injuries, Cell Count, Cultured Cells, Developmental Gene Expression Regulation, Mammalian Embryo, Membrane Glycoproteins, Nerve Growth Factor Receptors, Nerve Tissue Proteins, Neurons, Retina, Signal Transduction, Superior Cervical Ganglion, Time Factors, Tyrosine 3-Monooxygenase, Vesicular Transport Adaptor Proteins, Animals, Mice
Abstract: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.
ISSN:1097-6256
Publisher:Nature Publishing Group (U.S.A.)
Item Type:Article

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