The C. elegans BRCA2-ALP/Enigma Complex Regulates Axon Regeneration via a Rho GTPase-ROCK-MLC Phosphorylation Pathway

Cell Rep. 2018 Aug 14;24(7):1880-1889. doi: 10.1016/j.celrep.2018.07.049.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Axotomy / methods
  • Caenorhabditis elegans / genetics*
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins / genetics*
  • Caenorhabditis elegans Proteins / metabolism
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation
  • LIM Domain Proteins / genetics*
  • LIM Domain Proteins / metabolism
  • Motor Neurons / metabolism
  • Motor Neurons / pathology
  • Myosin Light Chains / genetics*
  • Myosin Light Chains / metabolism
  • Nerve Regeneration / genetics*
  • Neuronal Outgrowth / genetics
  • Neuronal Plasticity / genetics
  • Phosphorylation
  • Protein Binding
  • Signal Transduction
  • rho GTP-Binding Proteins / genetics*
  • rho GTP-Binding Proteins / metabolism
  • rho-Associated Kinases / genetics*
  • rho-Associated Kinases / metabolism


  • ALP-1 protein, C elegans
  • Adaptor Proteins, Signal Transducing
  • BRC-2 protein, C elegans
  • Caenorhabditis elegans Proteins
  • DNA-Binding Proteins
  • LIM Domain Proteins
  • MLC-4 protein, C elegans
  • Myosin Light Chains
  • LET-502 protein, C elegans
  • rho-Associated Kinases
  • RHO-1 protein, C elegans
  • rho GTP-Binding Proteins