Few studies have exploited the power of genetics and functional genomics to understand the mechanisms of regrowth of axons following injury. We have developed femtosecond laser axotomy to cut single axons in intact living C. elegans animals. Severed axons of several C. elegans cell types show robust regrowth and functional recovery. We have shown that several factors, including cell type, position of axotomy and life stage, can regulate whether axons regrow after injury. Conserved signaling pathways, including cyclic AMP signaling and ephrin signaling, regulate regenerative growth of axons. We also found an unexpected role for synaptic branches in regulating axon regrowth. The tractable genetic and genomic tools available in C. elegans facilitate large scale screens for new regeneration genes. A pilot screen has uncovered several new genes that promote or repress regenerative growth. Our three specific Aims build on these preliminary results: First, we will dissect the mechanism by which the synaptic branch regulates regeneration in mechanosensory neurons. We hypothesize that the synaptic branch point contains a sorting area that regulates membrane and organelle traffic after injury. We will analyze the transport of motors and cargoes required for regrowth and will specifically test the role of the Liprin pathway in promoting regrowth. Second we will define how cAMP signaling promotes C. elegans neuronal regeneration. We will test whether cAMP or its effectors are required for regrowth. We will examine the effects of axotomy on cAMP dynamics in vivo. We will test the role of a putative cAMP-regulated transcription factor that we have found is essential for regeneration. Third, we will perform a large scale functional genomic screen to identify new genes with roles in regenerative axon growth. The mechanisms of genes with strong pro- or anti-regeneration roles will be studied in detail. Relevance: This work will yield a systematic understanding of the pathways that regulate axon regeneration after injury in a simple model system. Knowledge of the conserved mechanisms controlling axon regeneration will allow their manipulation in therapies for nervous system disease and injury.

Public Health Relevance

We will analyze the molecular and genetic mechanisms underlying nerve regeneration in the nematode C. elegans. Specifically, we will define the roles of trafficking at axonal branch points and the function of cyclic AMP signaling. We will perform a large scale screen to discover novel genes involved in regenerative growth of neurons. The results will further our understanding of nerve regrowth and will aid therapies for trauma and disease of the nervous system.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
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Owens, David F
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University of California San Diego
Schools of Arts and Sciences
La Jolla
United States
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Tang, Ngang Heok; Jin, Yishi (2018) Shaping neurodevelopment: distinct contributions of cytoskeletal proteins. Curr Opin Neurobiol 51:111-118
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:
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
Kim, Kyung Won; Jin, Yishi (2015) Neuronal responses to stress and injury in C. elegans. FEBS Lett 589:1644-52
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:
Hubert, Thomas; Wu, Zilu; Chisholm, Andrew D et al. (2014) S6 kinase inhibits intrinsic axon regeneration capacity via AMP kinase in Caenorhabditis elegans. J Neurosci 34:758-63
Chuang, Marian; Goncharov, Alexandr; Wang, Shaohe et al. (2014) The microtubule minus-end-binding protein patronin/PTRN-1 is required for axon regeneration in C. elegans. Cell Rep 9:874-83
Chisholm, Andrew D (2013) Cytoskeletal dynamics in Caenorhabditis elegans axon regeneration. Annu Rev Cell Dev Biol 29:271-97

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