Laminin and beta 1 integrins are crucial for normal mammary gland development in the mouse

We have examined the role of integrin-extracellular matrix interactions in the morphogenesis of ductal structures in vivo using the developing mouse m ammary gland as a model. At puberty, ductal growth from terminal end buds r esults in an arborescent network that eventually fills the gland, whereupon the buds shrink in size and become mitotically inactive. End buds are surr ounded by a basement membrane, which we show contains laminin-l and collage n IV. To address the role of cell-matrix interactions in gland development, pellets containing function-perturbing anti-beta 1 integrin, anti-alpha 6 integrin, and anti-laminin antibodies respectively were implanted into mamm ary glands at puberty. Blocking beta 1 integrins dramatically reduced both the number of end buds per gland and the extent of the mammary ductal netwo rk, compared with controls. These effects were specific to the end buds sin ce the rest of the gland architecture remained intact, Reduced development was still apparent after 6 days, but end buds subsequently reappeared, indi cating that the inhibition of beta 1 integrins was reversible. Similar resu lts were obtained with anti-laminin antibodies. In contrast, no effect on m orphogenesis in vivo was seen with anti-alpha 6 integrin antibody, suggesti ng that ab is not the important partner for beta 1 in this system. The stud ies with beta 1 integrin were confirmed in a culture model of ductal morpho genesis, where we show that hepatocyte growth factor (HGF)-induced tubuloge nesis is dependent on functional beta 1 integrins. Thus integrins and HGF c ooperate to regulate ductal morphogenesis. We propose that both laminin and beta 1 integrins are required to permit cellular traction through the stro mal matrix and are therefore essential for maintaining end bud structure an d function in normal pubertal mammary gland development, (C) 1999 Academic Press.