title: Target-derived neurotrophins coordinate transcription and transport of bclw to prevent axonal degeneration.
abstract: Establishment of neuronal circuitry depends on both formation and refinement of neural connections. During this process, target-derived neurotrophins regulate both transcription and translation to enable selective axon survival or elimination. However, it is not known whether retrograde signaling pathways that control transcription are coordinated with neurotrophin-regulated actions that transpire in the axon. Here we report that target-derived neurotrophins coordinate transcription of the antiapoptotic gene bclw with transport of bclw mRNA to the axon, and thereby prevent axonal degeneration in rat and mouse sensory neurons. We show that neurotrophin stimulation of nerve terminals elicits new bclw transcripts that are immediately transported to the axons and translated into protein. Bclw interacts with Bax and suppresses the caspase6 apoptotic cascade that fosters axonal degeneration. The scope of bclw regulation at the levels of transcription, transport, and translation provides a mechanism whereby sustained neurotrophin stimulation can be integrated over time, so that axonal survival is restricted to neurons connected within a stable circuit.
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Katharina E
authors.initials: KE
authors.lastname: Cosker
authors.forename: Maria F
authors.initials: MF
authors.lastname: Pazyra-Murphy
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Fenstermacher
authors.forename: Rosalind A
authors.initials: RA
authors.lastname: Segal
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D001370:Axonal Transport / Q000187:drug effects / Q000502:physiology*; D001369:Axons / Q000187:drug effects / Q000502:physiology; D053178:Caspase 6 / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D006801:Humans; D008297:Male; D051379:Mice; D009410:Nerve Degeneration / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D009414:Nerve Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D011247:Pregnancy; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011984:Sensory Receptor Cells / Q000166:cytology / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D051020:bcl-X Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C494813:Bcl2l1 protein, rat; C101155:Bcl2l2 protein, mouse; D009414:Nerve Growth Factors; D011506:Proteins; D012333:RNA, Messenger; D051020:bcl-X Protein; C505516:Casp6 protein, mouse; C505518:Casp6 protein, rat; D053178:Caspase 6