Target derived neurotrophins (NTs) are required both for survival of the axon that encounters these ligands and for survival of the remote cell body. Much progress has been made in understanding how NT signals promote cell body survival. However, survival or degeneration of axons is controlled by molecular components that overlap with, but are not identical to, those that regulate cell body survival and death. Therefore an important unresolved question is how target derived NTs engage regulatory components to foster axonal survival and prevent axonal degeneration during development and throughout life. In preliminary studies, my colleagues and I identified bclw (or bcl2l2) as the bcl2 family member critical for NT-dependent axonal viability. Bclw is the bcl2 family member that is enriched in axons, bclw prevents progressive axonal degeneration in mouse models, and bclw is neuroprotective against ?-amyloid toxicity. We demonstrated that bclw is a retrograde response gene (RRG), which is selectively upregulated by NT stimulation of distal axons. Surprisingly, mRNA for bclw is present in axons as well as in cell bodies, and NT stimulation of distal axons increases the levels of bclw mRNAs in both locations. To understand how NTs regulate axonal viability and prevent degeneration we will determine how NT stimulation of distal axons coordinately regulates transcription, transport and translation of bclw mRNA to adjust the level of axonal bclw, and thereby preserve the long axons connecting a functioning circuit. We have three aims to test our model for NT regulation of axonal survival pathways, and to probe the implications for neurologic disorders characterized by axonal degeneration.
Aim 1. To test the hypothesis that NT stimulation of axons promotes transcription and axonal transport of newly synthesized bclw mRNAs.
Aim 2. To test the hypothesis that the RNA binding protein SFPQ is critical for bclw regulation.
Aim 3. To test the hypothesis that bclw is locally translated in axons to promote viability of long axons. Together these studies will provide a new understanding of how NT signaling functions within the spatial constraints of the developing and mature nervous system. Recent studies have focused attention on the importance of axonal degeneration for degenerative disorders, including peripheral neuropathies, ALS and Alzheimer's disease;our studies will identify pathways that support axonal health and are likely to be affected in such disorders. Furthermore, interventions that engage these NT-dependent pathways and preserve connected neurons within a functional circuit have great therapeutic potential in diverse neurologic diseases.

Public Health Relevance

Many degenerative disorders including Alzheimer's Disease and Sensory Neuropathies involve the dying back of axons before the changes in cell bodies. We have shown that Bclw is a pro-survival component that is found in the axons, and prevents axons from dying. In these studies, we will ask how levels of Bclw in axons are regulated by Nerve growth factors. Bclw has been shown to be protective against b-amyloid in Alzheimers'and to protect animals from neuropathy, therefore these studies may provide new approaches in these degenerative disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS050674-07
Application #
8259148
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Mamounas, Laura
Project Start
2004-12-01
Project End
2016-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
7
Fiscal Year
2012
Total Cost
$373,255
Indirect Cost
$154,505
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Cosker, Katharina E; Segal, Rosalind A (2014) Neuronal signaling through endocytosis. Cold Spring Harb Perspect Biol 6:
Pease, Sarah E; Segal, Rosalind A (2014) Preserve and protect: maintaining axons within functional circuits. Trends Neurosci 37:572-82
Cosker, Katharina E; Pazyra-Murphy, Maria F; Fenstermacher, Sara J et al. (2013) Target-derived neurotrophins coordinate transcription and transport of bclw to prevent axonal degeneration. J Neurosci 33:5195-207
Courchesne, Stephanie L; Pazyra-Murphy, Maria F; Lee, Daniel J et al. (2011) Neuromuscular junction defects in mice with mutation of dynein heavy chain 1. PLoS One 6:e16753
Fainzilber, Mike; Budnik, Vivian; Segal, Rosalind A et al. (2011) From synapse to nucleus and back again--communication over distance within neurons. J Neurosci 31:16045-8
Courchesne, Stephanie L; Karch, Christoph; Pazyra-Murphy, Maria F et al. (2011) Sensory neuropathy attributable to loss of Bcl-w. J Neurosci 31:1624-34
Cosker, Katharina E; Segal, Rosalind A (2010) The longer U(T)R, the further you go. Nat Neurosci 13:273-5
Pazyra-Murphy, Maria F; Hans, Aymeric; Courchesne, Stephanie L et al. (2009) A retrograde neuronal survival response: target-derived neurotrophins regulate MEF2D and bcl-w. J Neurosci 29:6700-9
Cosker, Katharina E; Courchesne, Stephanie L; Segal, Rosalind A (2008) Action in the axon: generation and transport of signaling endosomes. Curr Opin Neurobiol 18:270-5
Ha, Junghoon; Lo, Kevin W-H; Myers, Kenneth R et al. (2008) A neuron-specific cytoplasmic dynein isoform preferentially transports TrkB signaling endosomes. J Cell Biol 181:1027-39

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