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Articles, Neurobiology of Disease

Target-Derived Neurotrophins Coordinate Transcription and Transport of Bclw to Prevent Axonal Degeneration

Katharina E. Cosker, Maria F. Pazyra-Murphy, Sara J. Fenstermacher and Rosalind A. Segal
Journal of Neuroscience 20 March 2013, 33 (12) 5195-5207; https://doi.org/10.1523/JNEUROSCI.3862-12.2013
Katharina E. Cosker
1Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, and
2Departments of Cancer Biology and
3Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215
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Maria F. Pazyra-Murphy
1Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, and
2Departments of Cancer Biology and
3Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215
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Sara J. Fenstermacher
1Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, and
2Departments of Cancer Biology and
3Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215
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Rosalind A. Segal
1Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, and
2Departments of Cancer Biology and
3Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215
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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.

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The Journal of Neuroscience: 33 (12)
Journal of Neuroscience
Vol. 33, Issue 12
20 Mar 2013
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Target-Derived Neurotrophins Coordinate Transcription and Transport of Bclw to Prevent Axonal Degeneration
Katharina E. Cosker, Maria F. Pazyra-Murphy, Sara J. Fenstermacher, Rosalind A. Segal
Journal of Neuroscience 20 March 2013, 33 (12) 5195-5207; DOI: 10.1523/JNEUROSCI.3862-12.2013

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Target-Derived Neurotrophins Coordinate Transcription and Transport of Bclw to Prevent Axonal Degeneration
Katharina E. Cosker, Maria F. Pazyra-Murphy, Sara J. Fenstermacher, Rosalind A. Segal
Journal of Neuroscience 20 March 2013, 33 (12) 5195-5207; DOI: 10.1523/JNEUROSCI.3862-12.2013
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