Perturbation of beta1-integrin function alters the development of murine mammary gland.
The expression of a transgene coding for a chimeric molecule, containing the cytoplasmic and transmembrane domains of the beta1-integrin chain and the extracellular domain of the T-cell differentiation antigen CD4, was targeted to the mouse mammary gland by the mouse mammary tumor virus (MMTV) promoter. The chimera does not interact with the extracellular ligands; however, its expression in cultured cells was shown to interfere with focal adhesion kinase (FAK) phosphorylation following ligation of endogenous beta1-integrin. Therefore, expression of the transgenic protein on the cell surface should uncouple adhesion from intracellular events associated with the beta1-cytoplasmic domain and thus perturb beta1-integrin functions. Although most of the transgenic females were able to lactate, their mammary glands had a phenotype clearly distinct from that of wild-type mice. At mid-pregnancy and the beginning of lactation, transgenic glands were underdeveloped and the epithelial cell proliferation rates were decreased, while the apoptosis levels were higher than in wild-type glands. In lactation, the amounts of the whey acidic protein (WAP) and beta-casein gene transcripts were diminished, and the basement membrane component, laminin and the beta4-integrin chain accumulated at the lateral surface of luminal epithelial cells, revealing defects in polarization. Our observations prove that in vivo, beta1-integrins are involved in control of proliferation, apoptosis, differentiation and maintenance of baso-apical polarity of mammary epithelial cells, and therefore are essential for normal mammary gland development and function.
Faraldo
M M
MM
UMR 144, CNRS-Institut Curie, Section de Recherche, 26, rue d'Ulm, 75248, Paris, Cedex 05, France.
Deugnier
M A
MA
Lukashev
M
M
Thiery
J P
JP
Glukhova
M A
MA
D000818:Animals; D017209:Apoptosis; D015704:CD4 Antigens / Q000235:genetics; D002454:Cell Differentiation; D016764:Cell Polarity; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D019012:Integrin beta1 / Q000235:genetics / Q000502:physiology*; D007774:Lactation; D008321:Mammary Glands, Animal / Q000033:anatomy & histology / Q000166:cytology / Q000254:growth & development*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011247:Pregnancy; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology
D015704:CD4 Antigens; D019012:Integrin beta1; D011993:Recombinant Fusion Proteins