MAMMARY-GLAND MORPHOGENESIS IS INHIBITED IN TRANSGENIC MICE THAT OVEREXPRESS CELL-SURFACE BETA-1,4-GALACTOSYLTRANSFERASE

Mammary gland morphogenesis is facilitated by a precise sequence of ce ll-cell and cell-matrix interactions, which are mediated in part throu gh a variety of cell surface receptors and their ligands (Boudreau, N. , Myers, C. and Bissell, M. J. (1995), Trends in Cell Biology 5, 1-4), Cell surface beta 1,4-galactosyltransferase (GalTase) is one receptor that participates in a variety of cell-cell and cell-matrix interacti ons during fertilization and development, including mammary epithelial cell-matrix interactions (Barcellos-Hoff, M. H. (1992), Exp, Cell Res , 201, 225-234), To analyze GalTase function during mammary gland morp hogenesis in vivo, we created transgenic animals that overexpress the long isoform of GalTase under the control of a heterologous promoter, As expected, mammary epithelial cells from transgenic animals had 2.3 times more GalTase activity on their cell surface than did wild-type c ells, Homozygous transgenic females from multiple independent lines fa iled to lactate, whereas transgenic mice overexpressing the Golgi-loca lized short isoform of GalTase lactated normally, Glands from transgen ic females overexpressing surface GalTase were characterized by abnorm al and reduced ductal development with a concomitant reduction in alve olar expansion during pregnancy, The phenotype was not due to a defect in proliferation, since the mitotic index for transgenic and wild-typ e glands was similar, Morphological changes were accompanied by a dram atic reduction in the expression of milk-specific proteins, Immunohist ochemical markers for epithelia and myoepithelia demonstrated that bot h cell types were present. To better understand how overexpression of surface GalTase impairs ductal morphogenesis, primary mammary epitheli al cultures were established on basement membranes, Cultures derived f rom transgenic mammary glands were unable to form anastomosing network s of epithelial cells and failed to express milk-specific proteins, un like wild-type mammary cultures that formed epithelial tubules and exp ressed milk proteins, Our results suggest that cell surface GalTase is an important mediator of mammary cell interaction with the extracellu lar matrix, Furthermore, perturbing surface GalTase levels inhibits th e expression of mammary-specific gene products, implicating GalTase as a component of a receptor-mediated signal transduction pathway requir ed for normal mammary gland differentiation.