Enhanced branching morphogenesis in mammary glands of mice lacking cell surface β1, 4-galactosyltransferase

Abstract

Development of the mammary gland is influenced both by the systemic hormonal environment and locally through cell - cell and cell - extracellular matrix (ECM) interactions. We have previously demonstrated aberrant mammary gland morphogenesis in transgenic mice with elevated levels of the long isoform of β1, 4-galactosyltransferase 1 (Ga1T), a proportion of which is targeted to the plasma membrane, where it plays a role in cell - ECM interactions. Here, we show that mammary glands of mice lacking the long Ga1t isoform exhibit a complementary phenotype. Cell-surface Ga1T activity was reduced by over 60%, but because the short Ga1t isoform is intact, total Ga1t activity was reduced only slightly relative to wild type. Mammary glands from long Ga1T-null mice were characterized by excess branching, and this phenotype was accompanied by altered expression of laminin chains. Laminin α1 and α3 were reduced 2.4- and 3.0-fold, respectively, while expression of laminin γ2 was elevated 2.3-fold. The expression and cleavage of laminin γ2 have been correlated with branching and cell migration, and Western blotting revealed an altered pattern in γ2 cleavage products in long Ga1T-null mammary glands. We then examined the expression of metalloproteases that cleave laminins or that have been shown to play a role in mammary gland morphogenesis. Expression of MT1-MMP, a membrane-bound protease that can cleave laminin γ2, was elevated 5.5-fold in the long Ga1T-nulls. MMP 7 was also elevated 5.1-fold. Our results suggest that expression of surface Ga1t is important for the proper regulation of matrix expression and deposition, which in turn regulates the proper branching morphogenesis of the mammary epithelial ductal system. © 2002 Elsevier Science (USA).