Roles for the pro-neurotrophin receptor sortilin in neuronal development, aging and brain injury.
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.
Jansen
Pernille
P
MIND Center, Department of Medical Biochemistry, Ole Worms Allé 1170, Aarhus University, DK-8000 Aarhus C, Denmark.
Giehl
Klaus
K
Nyengaard
Jens R
JR
Teng
Kenneth
K
Lioubinski
Oleg
O
Sjoegaard
Susanne S
SS
Breiderhoff
Tilman
T
Gotthardt
Michael
M
Lin
Fuyu
F
Eilers
Andreas
A
Petersen
Claus M
CM
Lewin
Gary R
GR
Hempstead
Barbara L
BL
Willnow
Thomas E
TE
Nykjaer
Anders
A
D033942:Adaptor Proteins, Vesicular Transport; D000375:Aging / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology; D002452:Cell Count / Q000379:methods; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000502:physiology*; D009474:Neurons / Q000145:classification / Q000502:physiology*; D017475:Receptors, Nerve Growth Factor / Q000172:deficiency; D012160:Retina / Q000166:cytology / Q000196:embryology; D015398:Signal Transduction / Q000502:physiology; D017783:Superior Cervical Ganglion / Q000166:cytology; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D000099183:Sortilin
D033942:Adaptor Proteins, Vesicular Transport; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D017475:Receptors, Nerve Growth Factor; D014446:Tyrosine 3-Monooxygenase; D000099183:Sortilin; C517634:Ngfr protein, mouse