The overall goal of this project is to use the genetically tractable model organism C. elegans to dissect the molecular basis of axon regeneration after injury. The small size, transparent body and simple anatomy of C. elegans allows single axons to be severed in vivo and their regrowth studied in depth. In the prior funding period we used large- scale genetic screens in C. elegans to discover conserved genes and pathways that play regrowth-promoting or regrowth-inhibiting roles in vivo. Many of these pathways are distinct from those involved in developmental axon outgrowth. Our large scale screens and analysis of genetic interactions have led to models for the function of these regrowth factors that we will test mechanistically in this proposal. We will define the roles of ne genes that affect regrowth via axonal microtubule dynamics. We will investigate the role of membrane trafficking regulators in axon regrowth. Results from this work will elucidate intrinsic mechanisms that allow mature axons to regrow after damage. In vertebrates, peripheral nerves are capable of regrowth, yet recovery after peripheral nerve trauma is often incomplete. Improved knowledge of regrowth mechanisms could also inform our understanding of why other neurons do not regrow. The mammalian CNS is only minimally capable of regeneration after injury, reflecting the combined effects of an inhibitory environment and of reduced intrinsic regrowth capacity. Our work addresses intrinsic mechanisms that promote or inhibit axon regrowth, a high priority for this field. Some signaling pathways have conserved roles in axon regrowth, suggesting analysis of C. elegans axon regrowth has implications for understanding axon repair mechanisms in medically relevant situations.

Public Health Relevance

The goal of this work is to define fundamental mechanisms of how axons of mature neurons regrow after damage. We use an anatomically simple and genetically tractable model, the nematode C. elegans, to find conserved genes that affect the ability of axons to regrow after injury. These genes include signaling molecules, regulators of the microtubule cytoskeleton, and regulators of membrane traffic. A better understanding of the roles of these molecules in a simple model of regrowth could improve our ability to manipulate the intrinsic growth capacity of damaged axons in therapeutic settings.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
High Priority, Short Term Project Award (R56)
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Special Emphasis Panel (ZRG1)
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Jakeman, Lyn B
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University of California San Diego
Schools of Arts and Sciences
La Jolla
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Kim, Kyung Won; Tang, Ngang Heok; Andrusiak, Matthew G et al. (2018) A Neuronal piRNA Pathway Inhibits Axon Regeneration in C. elegans. Neuron 97:511-519.e6
Chen, Lizhen; Liu, Zhijie; Zhou, Bing et al. (2016) CELF RNA binding proteins promote axon regeneration in C. elegans and mammals through alternative splicing of Syntaxins. Elife 5:
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Chen, Lizhen; Chuang, Marian; Koorman, Thijs et al. (2015) Axon injury triggers EFA-6 mediated destabilization of axonal microtubules via TACC and doublecortin like kinase. Elife 4:
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