Dynein motors transport activated Trks to promote survival of target-dependent neurons.
Mutations that alter dynein function are associated with neurodegenerative diseases, but it is not known why defects in dynein-dependent transport impair neuronal survival. Here we show that dynein function in axons is selectively required for the survival of neurons that depend on target-derived neurotrophins. Stimulation of axon terminals with neurotrophins causes internalization of neurotrophin receptors (Trks). Using real-time imaging of fluorescently tagged Trks, we show that dynein is required for rapid transport of internalized, activated receptors from axon terminals to remote cell bodies. When dynein-based transport is inhibited, neurotrophin stimulation of axon terminals does not support survival. These studies indicate that defects in dynein-based transport reduce trafficking of activated Trks and thereby obstruct the prosurvival effect of target-derived trophic factors, leading to degeneration of target-dependent neurons.
Heerssen
Heather M
HM
Department of Neurobiology, Harvard Medical School and Department of Pediatric Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA.
Pazyra
Maria F
MF
Segal
Rosalind A
RA
D000818:Animals; D001370:Axonal Transport / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004398:Dyneins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017475:Receptors, Nerve Growth Factor / Q000819:agonists / Q000378:metabolism*
D009414:Nerve Growth Factors; D017475:Receptors, Nerve Growth Factor; D004398:Dyneins