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.

1. MIND Center, Department of Medical Biochemistry, Ole Worms Allé 1170, Aarhus University, DK-8000 Aarhus C, Denmark.
2. Department of Cell Biology and University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
3. MIND Center, Stereology and Electron Microscopy Research Laboratory, Ole Worms Allé 1185, Aarhus University, DK-8000 Aarhus C, Denmark.
4. Weill Medical College of Cornell University, New York, New York 10021, USA.
5. Max Delbrueck Center for Molecular Medicine, Robert-Rössle Strasse 10, D-13125 Berlin, Germany.

Correspondence to: Thomas E Willnow⁵ e-mail: willnow@mdc-berlin.de

Correspondence to: Anders Nykjaer¹ e-mail: an@biokemi.au.dk

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