The goal of this work is to define how axons regrow and reconnect after injury, focusing on molecular regulators acting within individual axons. Our model system is the simple animal C. elegans, in which single axons can be severed and regrow in vivo in a generally permissive environment. We have used large-scale genetic screens to discover conserved genes that promote or repress axon regrowth, most of which are not involved in developmental axon outgrowth. We propose to examine in depth the roles and interactions of three new regrowth-inhibiting pathways revealed from screening. First, we will dissect the roles of a conserved regulator of axonal sprouting that may regulate neuronal lipid metabolism. Second, we will examine how a highly conserved kinase pathway inhibits axon regrowth. Finally, we will elucidate the role of mRNA decay regulators in axonal regrowth and their potential link to mitochondrial function. Results from this work will elucidate intrinsic mechanisms that allow mature axons to respond to injury and regrow after damage. In vertebrates, peripheral nerves are capable of regrowth, yet recovery after peripheral nerve trauma is often slow and incomplete. The human 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 in organisms with high intrinsic regrowth capacity will also inform our understanding of why CNS neurons do not regrow. Many C. elegans pathways have been found to have conserved roles in axon regrowth, indicating the mechanisms underlying C. elegans axon regrowth will continue to yield insights into general principles of neuronal repair.

Public Health Relevance

Nervous systems have a remarkable ability to repair themselves after injury or trauma. Simple model nervous systems offer tractable entry points to understand the molecular basis of such repair processes. Studies in this application will elucidate the functions of selected conserved regulators of axonal regeneration. The resulting findings will lead to better understanding of how neurons repair themselves and how such repair factors might be modulated therapeutically.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS093588-06
Application #
9929052
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Bambrick, Linda Louise
Project Start
2015-07-15
Project End
2024-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
6
Fiscal Year
2020
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
Tang, Ngang Heok; Jin, Yishi (2018) Shaping neurodevelopment: distinct contributions of cytoskeletal proteins. Curr Opin Neurobiol 51:111-118
Noblett, Nathaniel; Wu, Zilu; Ding, Zhao Hua et al. (2018) DIP-2 suppresses ectopic neurite sprouting and axonal regeneration in mature neurons. J Cell Biol :
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
Kim, Kyung Won; Tang, Ngang Heok; Piggott, Christopher A et al. (2018) Expanded genetic screening in Caenorhabditis elegans identifies new regulators and an inhibitory role for NAD+ in axon regeneration. Elife 7:
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
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
He, Zhigang; Jin, Yishi (2016) Intrinsic Control of Axon Regeneration. Neuron 90:437-51
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:
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:

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