PERTURBATION OF BETA-1-INTEGRIN FUNCTION ALTERS THE DEVELOPMENT OF MURINE MAMMARY-GLAND

The expression of a transgene coding for a chimeric molecule, containi ng the cytoplasmic and transmembrane domains of the beta 1-integrin ch ain and the extracellular domain of the T-cell differentiation antigen CD4, was targeted to the mouse mammary gland by the mouse mammary tum or virus (MMTV) promoter. The chimera does not interact with the extra cellular ligands; however, its expression in cultured cells was shown to interfere with focal adhesion kinase (FAK) phosphorylation followin g ligation of endogenous beta 1-integrin, Therefore, expression of the transgenic protein on the cell surface should uncouple adhesion from intracellular events associated with the beta 1-cytoplasmic domain and thus perturb beta 1-integrin functions. Although most of the transgen ic 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 apoptos is levels were higher than in wild-type glands. In lactation, the amou nts of the whey acidic protein (WAP) and beta-casein gene transcripts were diminished, and the basement membrane component, laminin and the beta 4-integrin chain accumulated at the lateral surface of luminal ep ithelial cells, revealing defects in polarization. Our observations pr ove that in vivo, beta 1-integrins are involved in control of prolifer ation, apoptosis, differentiation and maintenance of baso-apical polar ity of mammary epithelial cells, and therefore are essential for norma l mammary gland development and function.