The DLK-1 kinase promotes mRNA stability and local translation in C. elegans synapses and axon regeneration

Cell. 2009 Sep 4;138(5):1005-18. doi: 10.1016/j.cell.2009.06.023.

Abstract

Growth cone guidance and synaptic plasticity involve dynamic local changes in proteins at axons and dendrites. The Dual-Leucine zipper Kinase MAPKKK (DLK) has been previously implicated in synaptogenesis and axon outgrowth in C. elegans and other animals. Here we show that in C. elegans DLK-1 regulates not only proper synapse formation and axon morphology but also axon regeneration by influencing mRNA stability. DLK-1 kinase signals via a MAPKAP kinase, MAK-2, to stabilize the mRNA encoding CEBP-1, a bZip protein related to CCAAT/enhancer-binding proteins, via its 3'UTR. Inappropriate upregulation of cebp-1 in adult neurons disrupts synapses and axon morphology. CEBP-1 and the DLK-1 pathway are essential for axon regeneration after laser axotomy in adult neurons, and axotomy induces translation of CEBP-1 in axons. Our findings identify the DLK-1 pathway as a regulator of mRNA stability in synapse formation and maintenance and also in adult axon regeneration.

Publication types

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

MeSH terms

  • Animals
  • Axons / metabolism
  • CCAAT-Enhancer-Binding Proteins / metabolism
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / metabolism*
  • Guanine Nucleotide Exchange Factors / metabolism
  • Intracellular Signaling Peptides and Proteins / metabolism
  • MAP Kinase Kinase Kinases / metabolism*
  • MAP Kinase Signaling System
  • Protein Biosynthesis
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA Stability*
  • Synapses*

Substances

  • CCAAT-Enhancer-Binding Proteins
  • Caenorhabditis elegans Proteins
  • Guanine Nucleotide Exchange Factors
  • Intracellular Signaling Peptides and Proteins
  • RPM-1 protein, C elegans
  • MAP-kinase-activated kinase 2
  • Protein-Serine-Threonine Kinases
  • DLK-1 protein, C elegans
  • MAP Kinase Kinase Kinases