Abstract
The ability of specific neurons to regenerate their axons after injury is governed by cell-intrinsic regeneration pathways. However, the mechanisms regulating axon regeneration are not well understood. Here, we identify the brc-2 gene encoding a homolog of the mammalian BRCA2 tumor suppressor as a regulator of axon regeneration in Caenorhabditis elegans motor neurons. We show that the RHO-1/Rho GTPase-LET-502/ROCK (Rho-associated coiled-coil kinase)-regulatory non-muscle myosin light-chain (MLC-4/MLC) phosphorylation signaling pathway regulates axon regeneration. BRC-2 functions between RHO-1 and LET-502, suggesting that BRC-2 is required for the activation of LET-502 by RHO-1-GTP. We also find that one component that interacts with BRC-2, the ALP (α-actinin-associated LIM protein)/Enigma protein ALP-1, is required for regeneration and acts between LET-502 and MLC-4 phosphorylation. Furthermore, we demonstrate that ALP-1 associates with LET-502 and MLC-4. Thus, ALP-1 serves as a platform to activate MLC-4 phosphorylation mediated by the RHO-1-LET-502 signaling pathway.
Keywords:
BRCA2; C. elegans; Rho kinase; axon regeneration.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics*
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Axotomy / methods
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Caenorhabditis elegans / genetics*
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Caenorhabditis elegans / metabolism
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Caenorhabditis elegans Proteins / genetics*
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Caenorhabditis elegans Proteins / metabolism
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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Gene Expression Regulation
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LIM Domain Proteins / genetics*
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LIM Domain Proteins / metabolism
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Motor Neurons / metabolism
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Motor Neurons / pathology
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Myosin Light Chains / genetics*
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Myosin Light Chains / metabolism
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Nerve Regeneration / genetics*
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Neuronal Outgrowth / genetics
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Neuronal Plasticity / genetics
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Phosphorylation
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Protein Binding
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Signal Transduction
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rho GTP-Binding Proteins / genetics*
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rho GTP-Binding Proteins / metabolism
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rho-Associated Kinases / genetics*
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rho-Associated Kinases / metabolism
Substances
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ALP-1 protein, C elegans
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Adaptor Proteins, Signal Transducing
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BRC-2 protein, C elegans
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Caenorhabditis elegans Proteins
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DNA-Binding Proteins
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LIM Domain Proteins
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MLC-4 protein, C elegans
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Myosin Light Chains
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LET-502 protein, C elegans
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rho-Associated Kinases
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RHO-1 protein, C elegans
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rho GTP-Binding Proteins