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  • The EMBO Journal (1998) 17, 3940 - 3951
  • doi:10.1093/emboj/17.14.3940

Cell cycle and adhesion defects in mice carrying a targeted deletion of the integrin bold beta4 cytoplasmic domain

Chiara Murgia1,2, Pamela Blaikie1, Nancy Kim1, Michael Dans1, Howard T. Petrie3,4 and Filippo G. Giancotti1,4

  1. Cellular Biochemistry and Biophysics Program, Graduate School of Medical Sciences, Cornell University, New York, NY 10021, USA
  2. Present address: Istituto Nazionale della Nutrizione, via Ardeatina, 546, Roma, Italy
  3. Immunology Program, Memorial Sloan-Kettering Cancer Center, Graduate School of Medical Sciences, Cornell University, New York, NY 10021, USA
  4. Sloan-Kettering Division, Graduate School of Medical Sciences, Cornell University, New York, NY 10021, USA

Correspondence to:

Filippo G. Giancotti, E-mail: F-Giancotti@ski.mskcc.org

Received 5 March 1998; Accepted 12 May 1998; Revised 12 May 1998

The cytoplasmic domain of the integrin beta4 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 beta4 cytoplasmic domain. Analysis of homozygous mutant mice indicates that the tail-less alpha6beta4 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 p27Kip. These findings indicate that the interactions mediated by the beta4 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.

  • Keywords:

    • blistering skin disease,
    • cell cycle,
    • gene targeting,
    • integrin,
    • signaling