Expanded genetic screening in caenorhabditis elegans identifies new regulators and an inhibitory role for NAD                         +                          in axon regeneration

Kyung Won Kim; Ngang Heok Tang; Christopher A. Piggott; Matthew G. Andrusiak; Seungmee Park; Ming Zhu; Naina Kurup; Salvatore J. Cherra; Zilu Wu; Andrew D. Chisholm; Yishi Jin

doi:10.7554/eLife.39756

Expanded genetic screening in caenorhabditis elegans identifies new regulators and an inhibitory role for NAD ⁺ in axon regeneration

Kyung Won Kim, Ngang Heok Tang, Christopher A. Piggott, Matthew G. Andrusiak, Seungmee Park, Ming Zhu, Naina Kurup, Salvatore J. Cherra, Zilu Wu, Andrew D. Chisholm, Yishi Jin

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

Abstract

The mechanisms underlying axon regeneration in mature neurons are relevant to the understanding of normal nervous system maintenance and for developing therapeutic strategies for injury. Here, we report novel pathways in axon regeneration, identified by extending our previous function-based screen using the C. elegans mechanosensory neuron axotomy model. We identify an unexpected role of the nicotinamide adenine dinucleotide (NAD ⁺ ) synthesizing enzyme, NMAT-2/NMNAT, in axon regeneration. NMAT-2 inhibits axon regrowth via cell-autonomous and non-autonomous mechanisms. NMAT-2 enzymatic activity is required to repress regrowth. Further, we find differential requirements for proteins in membrane contact site, components and regulators of the extracellular matrix, membrane trafficking, microtubule and actin cytoskeleton, the conserved Kelch-domain protein IVNS-1, and the orphan transporter MFSD-6 in axon regrowth. Identification of these new pathways expands our understanding of the molecular basis of axonal injury response and regeneration.

Original language	English
Article number	e39756
Journal	eLife
Volume	7
DOIs	https://doi.org/10.7554/eLife.39756
State	Published - Nov 1 2018

Bibliographical note

Funding Information:
We thank our members for valuable discussions and Laura Toy for assistance in strain construction. We thank Dr. S Mitani and National Bioresource Project of Japan, and the Caenorhabditis Genetics Center (funded by NIH Office of Research Infrastructure Programs P40 OD010440) for strains. KWK received an American Heart Association postdoctoral fellowship and Hallym University research funds (HRF-201809–014), MGA received a Canadian Institutes of Health Research Postdoctoral Fellowship (MFE-146808), and SJC was a receipient of NIH K99 (NS097638). This work was supported by NIH R01 grants to YJ, and ADC (NS057317 and NS093588).

Publisher Copyright:
© Kim et al.

ASJC Scopus subject areas

Neuroscience (all)
Biochemistry, Genetics and Molecular Biology (all)
Immunology and Microbiology (all)

Access to Document

10.7554/eLife.39756

Cite this

Kim, K. W., Tang, N. H., Piggott, C. A., Andrusiak, M. G., Park, S., Zhu, M., Kurup, N., Cherra, S. J., Wu, Z., Chisholm, A. D., & Jin, Y. (2018). Expanded genetic screening in caenorhabditis elegans identifies new regulators and an inhibitory role for NAD ⁺ in axon regeneration eLife, 7, Article e39756. https://doi.org/10.7554/eLife.39756

@article{3493fad93d42422f89d96206d42a84f5,

title = " Expanded genetic screening in caenorhabditis elegans identifies new regulators and an inhibitory role for NAD + in axon regeneration ",

abstract = " The mechanisms underlying axon regeneration in mature neurons are relevant to the understanding of normal nervous system maintenance and for developing therapeutic strategies for injury. Here, we report novel pathways in axon regeneration, identified by extending our previous function-based screen using the C. elegans mechanosensory neuron axotomy model. We identify an unexpected role of the nicotinamide adenine dinucleotide (NAD + ) synthesizing enzyme, NMAT-2/NMNAT, in axon regeneration. NMAT-2 inhibits axon regrowth via cell-autonomous and non-autonomous mechanisms. NMAT-2 enzymatic activity is required to repress regrowth. Further, we find differential requirements for proteins in membrane contact site, components and regulators of the extracellular matrix, membrane trafficking, microtubule and actin cytoskeleton, the conserved Kelch-domain protein IVNS-1, and the orphan transporter MFSD-6 in axon regrowth. Identification of these new pathways expands our understanding of the molecular basis of axonal injury response and regeneration.",

author = "Kim, {Kyung Won} and Tang, {Ngang Heok} and Piggott, {Christopher A.} and Andrusiak, {Matthew G.} and Seungmee Park and Ming Zhu and Naina Kurup and Cherra, {Salvatore J.} and Zilu Wu and Chisholm, {Andrew D.} and Yishi Jin",

note = "Funding Information: We thank our members for valuable discussions and Laura Toy for assistance in strain construction. We thank Dr. S Mitani and National Bioresource Project of Japan, and the Caenorhabditis Genetics Center (funded by NIH Office of Research Infrastructure Programs P40 OD010440) for strains. KWK received an American Heart Association postdoctoral fellowship and Hallym University research funds (HRF-201809–014), MGA received a Canadian Institutes of Health Research Postdoctoral Fellowship (MFE-146808), and SJC was a receipient of NIH K99 (NS097638). This work was supported by NIH R01 grants to YJ, and ADC (NS057317 and NS093588). Publisher Copyright: {\textcopyright} Kim et al.",

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Kim, KW, Tang, NH, Piggott, CA, Andrusiak, MG, Park, S, Zhu, M, Kurup, N, Cherra, SJ, Wu, Z, Chisholm, AD & Jin, Y 2018, ' Expanded genetic screening in caenorhabditis elegans identifies new regulators and an inhibitory role for NAD ⁺ in axon regeneration ', eLife, vol. 7, e39756. https://doi.org/10.7554/eLife.39756

Expanded genetic screening in caenorhabditis elegans identifies new regulators and an inhibitory role for NAD ⁺ in axon regeneration . / Kim, Kyung Won; Tang, Ngang Heok; Piggott, Christopher A. et al.
In: eLife, Vol. 7, e39756, 01.11.2018.

Research output: Contribution to journal › Article › peer-review

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AU - Kim, Kyung Won

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AU - Kurup, Naina

AU - Cherra, Salvatore J.

AU - Wu, Zilu

AU - Chisholm, Andrew D.

AU - Jin, Yishi

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N2 - The mechanisms underlying axon regeneration in mature neurons are relevant to the understanding of normal nervous system maintenance and for developing therapeutic strategies for injury. Here, we report novel pathways in axon regeneration, identified by extending our previous function-based screen using the C. elegans mechanosensory neuron axotomy model. We identify an unexpected role of the nicotinamide adenine dinucleotide (NAD + ) synthesizing enzyme, NMAT-2/NMNAT, in axon regeneration. NMAT-2 inhibits axon regrowth via cell-autonomous and non-autonomous mechanisms. NMAT-2 enzymatic activity is required to repress regrowth. Further, we find differential requirements for proteins in membrane contact site, components and regulators of the extracellular matrix, membrane trafficking, microtubule and actin cytoskeleton, the conserved Kelch-domain protein IVNS-1, and the orphan transporter MFSD-6 in axon regrowth. Identification of these new pathways expands our understanding of the molecular basis of axonal injury response and regeneration.

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