Enhanced Branching Morphogenesis in Mammary Glands of Mice Lacking Cell Surface 1,4-Galactosyltransferase

Authors: Steffgen K.; Dufraux K.; Hathaway H.

Source: Developmental Biology, Volume 244, Number 1, April 2002 , pp. 114-133(20)

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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 beta 1,4-galactosyltransferase 1 (GalT), 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 GalT isoform exhibit a complementary phenotype. Cell-surface GalT activity was reduced by over 60%, but because the short GalT isoform is intact, total GalT activity was reduced only slightly relative to wild type. Mammary glands from long GalT-null mice were characterized by excess branching, and this phenotype was accompanied by altered expression of laminin chains. Laminin alpha 1 and alpha 3 were reduced 2.4- and 3.0-fold, respectively, while expression of laminin gamma 2 was elevated 2.3-fold. The expression and cleavage of laminin gamma 2 have been correlated with branching and cell migration, and Western blotting revealed an altered pattern in gamma 2 cleavage products in long GalT-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 gamma 2, was elevated 5.5-fold in the long GalT-nulls. MMP 7 was also elevated 5.1-fold. Our results suggest that expression of surface GalT 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).