Cell cycle and adhesion defects in mice carrying a targeted deletion of the integrin beta4 cytoplasmic domain.
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 p27(Kip). 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.
Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
C
C
Murgia
P
P
Blaikie
N
N
Kim
M
M
Dans
H T
HT
Petrie
F G
FG
Giancotti
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology*; D000954:Antigens, Surface / Q000378:metabolism; D001485:Basement Membrane / Q000166:cytology; D002448:Cell Adhesion / Q000235:genetics*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics*; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003593:Cytoplasm / Q000737:chemistry; D003599:Cytoskeleton / Q000378:metabolism; D003896:Desmosomes; D004386:Duodenum / Q000166:cytology* / Q000196:embryology; D016109:Epidermolysis Bullosa, Junctional; D039161:Integrin alpha6beta4; D039663:Integrin beta4; D016023:Integrins / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology; D015603:Keratinocytes / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000032:analysis; D011708:Pylorus / Q000166:cytology; D017384:Sequence Deletion; D012867:Skin / Q000166:cytology* / Q000196:embryology; D025521:Tumor Suppressor Proteins; D000097794:Kalinin
D015703:Antigens, CD; D000954:Antigens, Surface; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D039161:Integrin alpha6beta4; D039663:Integrin beta4; D016023:Integrins; D008869:Microtubule-Associated Proteins; D025521:Tumor Suppressor Proteins; D000097794:Kalinin; C493961:Cdkn1b protein, mouse