PAK4 kinase is essential for embryonic viability and for proper neuronal development

Mol Cell Biol. 2003 Oct;23(20):7122-33. doi: 10.1128/MCB.23.20.7122-7133.2003.

Abstract

The serine/threonine kinase PAK4 is a target for the Rho GTPase Cdc42 and has been shown to regulate cell morphology and cytoskeletal organization in mammalian cells. To examine the physiological and developmental functions of PAK4, we have disrupted the PAK4 gene in mice. The absence of PAK4 led to lethality by embryonic day 11.5, a result most likely due to a defect in the fetal heart. Striking abnormalities were also evident in the nervous systems of PAK4-deficient embryos. These embryos had dramatic defects in neuronal development and axonal outgrowth. In particular, spinal cord motor neurons and interneurons failed to differentiate and migrate to their proper positions. This is probably related to the role for PAK4 in the regulation of cytoskeletal organization and cell and/or extracellular matrix adhesion. PAK4-null embryos also had defects in proper folding of the caudal portion of the neural tube, suggesting an important role for PAK4 in neural tube development.

Publication types

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

MeSH terms

  • Animals
  • Axons / metabolism
  • Blotting, Northern
  • Bromodeoxyuridine / pharmacology
  • Cell Adhesion
  • Cell Differentiation
  • Cell Line
  • Cell Movement
  • Cloning, Molecular
  • Cytoskeleton / metabolism
  • DNA, Complementary / metabolism
  • Extracellular Matrix / metabolism
  • Fluorescent Antibody Technique, Indirect
  • Genetic Vectors
  • Genotype
  • Heart / embryology
  • Humans
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Models, Genetic
  • Neural Crest / abnormalities
  • Neural Crest / cytology
  • Neural Crest / embryology
  • Neurons / metabolism
  • Neurons / pathology
  • Neurons / physiology*
  • Plasmids / metabolism
  • Polymerase Chain Reaction
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / physiology*
  • Spinal Cord / embryology
  • Time Factors
  • Tissue Distribution
  • cdc42 GTP-Binding Protein / metabolism*
  • p21-Activated Kinases

Substances

  • DNA, Complementary
  • PAK4 protein, human
  • Pak4 protein, mouse
  • Protein-Serine-Threonine Kinases
  • p21-Activated Kinases
  • cdc42 GTP-Binding Protein
  • Bromodeoxyuridine