Regulation of a DLK-1 and p38 MAP kinase pathway by the ubiquitin ligase RPM-1 is required for presynaptic development

Cell. 2005 Feb 11;120(3):407-20. doi: 10.1016/j.cell.2004.12.017.

Abstract

Synapses display a stereotyped ultrastructural organization, commonly containing a single electron-dense presynaptic density surrounded by a cluster of synaptic vesicles. The mechanism controlling subsynaptic proportion is not understood. Loss of function in the C. elegans rpm-1 gene, a putative RING finger/E3 ubiquitin ligase, causes disorganized presynaptic cytoarchitecture. RPM-1 is localized to the presynaptic periactive zone. We report that RPM-1 negatively regulates a p38 MAP kinase pathway composed of the dual leucine zipper-bearing MAPKKK DLK-1, the MAPKK MKK-4, and the p38 MAP kinase PMK-3. Inactivation of this pathway suppresses rpm-1 loss of function phenotypes, whereas overexpression or constitutive activation of this pathway causes synaptic defects resembling rpm-1(lf) mutants. DLK-1, like RPM-1, is localized to the periactive zone. DLK-1 protein levels are elevated in rpm-1 mutants. The RPM-1 RING finger can stimulate ubiquitination of DLK-1. Our data reveal a presynaptic role of a previously unknown p38 MAP kinase cascade.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Caenorhabditis elegans / embryology*
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans / ultrastructure
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Cell Differentiation / physiology
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism*
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism*
  • MAP Kinase Signaling System / physiology*
  • Microscopy, Electron, Transmission
  • Mitogen-Activated Protein Kinases / metabolism
  • Mutation / genetics
  • Nervous System / embryology
  • Nervous System / metabolism
  • Nervous System / ultrastructure
  • Presynaptic Terminals / metabolism*
  • Presynaptic Terminals / ultrastructure
  • Protein Structure, Tertiary / physiology
  • Ubiquitin / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • Caenorhabditis elegans Proteins
  • Guanine Nucleotide Exchange Factors
  • RPM-1 protein, C elegans
  • Ubiquitin
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • pmk-3 protein, C elegans
  • DLK-1 protein, C elegans
  • MAP Kinase Kinase Kinases
  • mitogen-activated protein kinase kinase kinase 12