Genetic Interactions Between Doublecortin and Doublecortin-Like Kinase in Neuronal Migration and Axon Outgrowth

Neuron. 2006 Jan 5;49(1):41-53. doi: 10.1016/j.neuron.2005.10.038.

Abstract

Although mutations in the human doublecortin gene (DCX) cause profound defects in cortical neuronal migration, a genetic deletion of Dcx in mice produces a milder defect. A second locus, doublecortin-like kinase (Dclk), encodes a protein with similar "doublecortin domains" and microtubule stabilization properties that may compensate for Dcx. Here, we generate a mouse with a Dclk mutation that causes no obvious migrational abnormalities but show that mice mutant for both Dcx and Dclk demonstrate perinatal lethality, disorganized neocortical layering, and profound hippocampal cytoarchitectural disorganization. Surprisingly, Dcx(-/y);Dclk(-/-) mutants have widespread axonal defects, affecting the corpus callosum, anterior commissure, subcortical fiber tracts, and internal capsule. Dcx/Dclk-deficient dissociated neurons show abnormal axon outgrowth and dendritic structure, with defects in axonal transport of synaptic vesicle proteins. Dcx and Dclk may directly or indirectly regulate microtubule-based vesicle transport, a process critical to both neuronal migration and axon outgrowth.

Publication types

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

MeSH terms

  • Animals
  • Animals, Newborn
  • Axons / physiology*
  • Axons / ultrastructure
  • Brain / abnormalities
  • Brain / embryology
  • Cell Movement / physiology*
  • Congenital Abnormalities / genetics
  • Congenital Abnormalities / mortality
  • Congenital Abnormalities / pathology
  • Dendrites / ultrastructure
  • Embryo, Mammalian / metabolism
  • Embryo, Mammalian / pathology
  • Mice
  • Mice, Knockout
  • Mice, Mutant Strains
  • Microtubule-Associated Proteins / genetics*
  • Microtubule-Associated Proteins / physiology
  • Neocortex / embryology
  • Nerve Tissue Proteins / deficiency
  • Neurons / physiology*
  • Neuropeptides / genetics*
  • Neuropeptides / physiology
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / physiology
  • RNA, Messenger / metabolism
  • Synaptic Vesicles / metabolism
  • Tissue Survival

Substances

  • Microtubule-Associated Proteins
  • Nerve Tissue Proteins
  • Neuropeptides
  • RNA, Messenger
  • doublecortin protein
  • Dcamkl1 protein, mouse
  • Protein-Serine-Threonine Kinases