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 analyses of genetic interactions have led to models for the function of these regrowth factors that we will test mechanistically in this proposal. We will dissect a signaling pathway that inhibits axon regrowth via axonal microtubule dynamics. We will investigate the role of membrane trafficking regulators in axon extension. 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 slow and incomplete. The mammalian CNS undergoes minimal regeneration after injury, reflecting the combined effects of an inhibitory environment and of reduced intrinsic regrowth capacity. Improved knowledge of regrowth mechanisms will also inform our understanding of why CNS neurons do not regrow. Our work addresses intrinsic mechanisms that promote or inhibit axon regrowth, a high priority for this field. Many 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 better understand how axons regrow after damage. The project uses a tractable model, the nematode C. elegans, to define novel mechanisms regulating axon regeneration after injury. Axon regrowth is influenced by the axonal microtubule cytoskeleton and by membrane trafficking. We propose to dissect mechanisms by which novel regulators of axon regrowth affect these processes in the context of growth cone formation and axon extension.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS093588-04
Application #
9473825
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Jakeman, Lyn B
Project Start
2015-07-15
Project End
2019-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California, San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Wang, Shaohe; Tang, Ngang Heok; Lara-Gonzalez, Pablo et al. (2017) A toolkit for GFP-mediated tissue-specific protein degradation in C. elegans. Development 144:2694-2701
Knowlton, Wendy M; Hubert, Thomas; Wu, Zilu et al. (2017) A Select Subset of Electron Transport Chain Genes Associated with Optic Atrophy Link Mitochondria to Axon Regeneration in Caenorhabditis elegans. Front Neurosci 11:263
Chisholm, Andrew D; Hutter, Harald; Jin, Yishi et al. (2016) The Genetics of Axon Guidance and Axon Regeneration in Caenorhabditis elegans. Genetics 204:849-882
Tang, Ngang Heok; Chisholm, Andrew D (2016) Regulation of Microtubule Dynamics in Axon Regeneration: Insights from C. elegans. F1000Res 5:
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:
He, Zhigang; Jin, Yishi (2016) Intrinsic Control of Axon Regeneration. Neuron 90:437-51
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: