Cdk5 phosphorylation of doublecortin ser297 regulates its effect on neuronal migration

Neuron. 2004 Jan 22;41(2):215-27. doi: 10.1016/s0896-6273(03)00852-3.

Abstract

Mutations in the doublecortin (DCX) gene in human or targeted disruption of the cdk5 gene in mouse lead to similar cortical lamination defects in the developing brain. Here we show that Dcx is phosphorylated by Cdk5. Dcx phosphorylation is developmentally regulated and corresponds to the timing of expression of p35, the major activating subunit for Cdk5. Mass spectrometry and Western blot analysis indicate phosphorylation at Dcx residue Ser297. Phosphorylation of Dcx lowers its affinity to microtubules in vitro, reduces its effect on polymerization, and displaces it from microtubules in cultured neurons. Mutation of Ser297 blocks the effect of Dcx on migration in a fashion similar to pharmacological inhibition of Cdk5 activity. These results suggest that Dcx phosphorylation by Cdk5 regulates its actions on migration through an effect on microtubules.

Publication types

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

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Movement / physiology
  • Cerebral Cortex / cytology
  • Cerebral Cortex / metabolism
  • Cyclin-Dependent Kinase 5
  • Cyclin-Dependent Kinases / metabolism
  • Cyclin-Dependent Kinases / physiology*
  • Humans
  • Image Processing, Computer-Assisted
  • Immunoprecipitation
  • In Situ Hybridization
  • Mice
  • Mice, Knockout
  • Microtubule-Associated Proteins / metabolism
  • Microtubule-Associated Proteins / physiology*
  • Microtubules / metabolism
  • Mutagenesis, Site-Directed
  • Nerve Tissue Proteins / physiology
  • Nervous System / growth & development
  • Neurons / physiology*
  • Neuropeptides / metabolism
  • Neuropeptides / physiology*
  • Phenotype
  • Phosphorylation
  • Purines / pharmacology
  • Retroviridae / genetics
  • Roscovitine
  • Serine / metabolism
  • Serine / physiology*
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Transfection

Substances

  • Microtubule-Associated Proteins
  • Nerve Tissue Proteins
  • Neuropeptides
  • Purines
  • doublecortin protein
  • neuronal Cdk5 activator (p25-p35)
  • Roscovitine
  • Serine
  • Cyclin-Dependent Kinase 5
  • CDK5 protein, human
  • Cdk5 protein, mouse
  • Cyclin-Dependent Kinases