Proneurotrophin-3 is a neuronal apoptotic ligand: evidence for retrograde-directed cell killing.
Although mature neurotrophins are well described trophic factors that elicit retrograde survival signaling, the precursor forms of neurotrophins (i.e., proneurotrophins) can function as high-affinity apoptotic ligands for selected neural populations. An outstanding question is whether target-derived proneurotrophins might affect neuronal survival/death decisions through a retrograde transport mechanism. Since neurotrophin-3 (NT-3) is highly expressed in non-neural tissues that receive peripheral innervation, we investigated the localized actions of its precursor (proNT-3) on sympathetic neurons in the present study. Pharmacological inhibition of intracellular furin proteinase activity in 293T cells resulted in proNT-3 release instead of mature NT-3, whereas membrane depolarization in cerebellar granule neurons stimulated endogenous proNT-3 secretion, suggesting that proNT-3 is an inducible bona fide ligand in the nervous system. Our data also indicate that recombinant proNT-3 induced sympathetic neuron death that is p75(NTR)- and sortilin-dependent, with hallmark features of apoptosis including JNK (c-Jun N-terminal kinase) activation and nuclear fragmentation. Using compartmentalized culture systems that segregate neuronal cell bodies from axons, proNT-3, acting within the distal axon compartment, elicited sympathetic neuron death and overrode the survival-promoting actions of NGF. Together, these results raise the intriguing possibility that dysregulation of proneurotrophin processing/release by innervated targets can be deleterious to the neurons projecting to these sites.
Yano
Hiroko
H
Molecular Neurobiology Program, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York 10016, USA.
Torkin
Risa
R
Martin
Laura Andrés
LA
Chao
Moses V
MV
Teng
Kenneth K
KK
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology*; D001370:Axonal Transport / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D005728:Ganglia, Sympathetic / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008024:Ligands; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000378:metabolism* / Q000503:physiopathology; D020932:Nerve Growth Factor / Q000378:metabolism / Q000494:pharmacology; D009420:Nervous System / Q000166:cytology / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D020933:Neurotrophin 3 / Q000378:metabolism*; D016716:PC12 Cells; D051381:Rats; D017475:Receptors, Nerve Growth Factor / Q000187:drug effects / Q000378:metabolism; D000099183:Sortilin
D033942:Adaptor Proteins, Vesicular Transport; D048031:JNK Mitogen-Activated Protein Kinases; D008024:Ligands; D020932:Nerve Growth Factor; D020933:Neurotrophin 3; D017475:Receptors, Nerve Growth Factor; D000099183:Sortilin; C517634:Ngfr protein, mouse