Epithelial tubulogenesis is responsible for the exquisitely intricate organization of functional units of parenchymal organs. We have previously demonstrated that hepatocyte growth factor (HGF--also known as scatter factor) is a stroma-derived epithelial morphogen, which induces tubulogenesis by kidney-derived epithelial cells in vitro. The mammary gland provides a particularly attractive model for the study of epithelial morphogenesis, since its development in postnatal life involves elongation and branching of epithelial tubules. The aim of the present studies was to assess the expression and modulation of HGF and its receptor c-Met in the rat mammary gland during pregnancy, lactation, and involution. By ribonuclease protection assay, we demonstrate that levels of both HGF and c-met transcripts are progressively reduced during pregnancy, are virtually undetectable during lactation, and increase during the phase of involution to prepregnancy levels. The reduction in HGF and c-met expression corresponds to periods in which functions other than tubulogenesis predominate in the mammary gland, namely alveologenesis (mid to late pregnancy) and milk protein synthesis (lactation). Using a murine mammary gland-derived epithelial cell line, we demonstrate that levels of c-met mRNA are significantly reduced by exogenously added prolactin, providing a possible explanation for the reduction in c-met in the rat mammary gland during lactation. The potential significance of down-regulation of HGF/c-met during lactation is discussed.