Cell cycle and adhesion defects in mice carrying a targeted deletion of the integrin β4 cytoplasmic domain

Chiara Murgia, Pamela Blaikie, Nancy Kim, Michael Dans, Howard T. Petrie, Filippo G. Giancotti

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129 Citations (Scopus)

Abstract

The cytoplasmic domain of the integrin β4 subunit mediates both association with the hemidesmosomal cytoskeleton and recruitment of the signaling adaptor protein Shc. To examine the significance of these interactions during development, we have generated mice carrying a targeted deletion of the β4 cytoplasmic domain. Analysis of homozygous mutant mice indicates that the tail-less α6β4 binds efficiently to laminin 5, but is unable to integrate with the cytoskeleton. Accordingly, these mice display extensive epidermal detachment at birth and die immmediately thereafter from a syndrome resembling the human disease junctional epidermolysis bullosa with pyloric atresia (PA-JEB). In addition, we find a significant proliferative defect. Specifically, the number of precursor cells in the intestinal epithelium, which remains adherent to the basement membrane, and in intact areas of the skin is reduced, and post-mitotic enterocytes display increased levels of the cyclin-dependent kinase inhibitor p27(Kip). These findings indicate that the interactions mediated by the β4 tail are crucial for stable adhesion of stratified epithelia to the basement membrane and for proper cell-cycle control in the proliferative compartments of both stratified and simple epithelia.

Original languageEnglish
Pages (from-to)3940-3951
Number of pages12
JournalThe EMBO Journal
Volume17
Issue number14
DOIs
Publication statusPublished - 15 Jul 1998
Externally publishedYes

Keywords

  • Blistering skin disease
  • Cell cycle
  • Gene targeting
  • Integrin
  • Signaling

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