Perturbation of beta 1-integrin function alters the development of murine mammary gland

Abstract

The expression of a transgene coding for a chimeric molecule, containing the cytoplasmic and transmembrane domains of the β1‐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 β1‐integrin. Therefore, expression of the transgenic protein on the cell surface should uncouple adhesion from intracellular events associated with the β1‐cytoplasmic domain and thus perturb β1‐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 β‐casein gene transcripts were diminished, and the basement membrane component, laminin and the β4‐integrin chain accumulated at the lateral surface of luminal epithelial cells, revealing defects in polarization. Our observations prove that in vivo, β1‐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.