p38 and a p38-interacting protein are critical for downregulation of E-cadherin during mouse gastrulation

Cell. 2006 Jun 2;125(5):957-69. doi: 10.1016/j.cell.2006.03.048.

Abstract

During vertebrate gastrulation, an epithelial to mesenchymal transition (EMT) is necessary for migration of mesoderm from the primitive streak. We demonstrate that p38 MAP kinase and a p38-interacting protein (p38IP) are critically required for downregulation of E-cadherin during gastrulation. In an ENU-mutagenesis screen we identified the droopy eye (drey) mutation, which affects splicing of p38IP. p38IP(drey) mutant embryos display incompletely penetrant defects in neural tube closure, eye development, and gastrulation. A stronger allele (p38IP(RRK)) exhibits gastrulation defects in which mesoderm migration is defective due to deficiency in E-cadherin protein downregulation in the primitive streak. We show that p38IP binds directly to p38 and is required for p38 activation in vivo. Moreover, both p38 and p38IP are required for E-cadherin downregulation during gastrulation. Finally, p38 regulates E-cadherin protein expression downstream from NCK-interacting kinase (NIK) and independently of the regulation of transcription by Fibroblast Growth Factor (Fgf) signaling and Snail.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alternative Splicing / genetics
  • Animals
  • Body Patterning / physiology*
  • Cadherins / genetics
  • Cadherins / metabolism*
  • Cells, Cultured
  • Down-Regulation / genetics*
  • Embryonic Development / physiology*
  • Eye Abnormalities / genetics
  • Eye Abnormalities / metabolism
  • Eye Abnormalities / physiopathology
  • Fibroblast Growth Factors / metabolism
  • Fibroblast Growth Factors / pharmacology
  • Gastrula / cytology
  • Gastrula / metabolism*
  • Intracellular Signaling Peptides and Proteins
  • Mesoderm / metabolism
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Molecular Sequence Data
  • Mutation / genetics
  • Neural Tube Defects / genetics
  • Neural Tube Defects / metabolism
  • Neural Tube Defects / physiopathology
  • Protein Binding / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Regulatory Elements, Transcriptional / drug effects
  • Regulatory Elements, Transcriptional / physiology
  • Snail Family Transcription Factors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • Cadherins
  • FAM48A protein, human
  • Intracellular Signaling Peptides and Proteins
  • Snail Family Transcription Factors
  • Transcription Factors
  • Fibroblast Growth Factors
  • MAP4K4 protein, human
  • Protein-Serine-Threonine Kinases
  • p38 Mitogen-Activated Protein Kinases

Associated data

  • GENBANK/AF093250
  • GENBANK/AF139179