SEQUENTIAL REQUIREMENT OF HEPATOCYTE GROWTH-FACTOR AND NEUREGULIN IN THE MORPHOGENESIS AND DIFFERENTIATION OF THE MAMMARY-GLAND

We have examined the role of two mesenchymal ligands of epithelial tyr osine kinase receptors in mouse mammary gland morphogenesis. In organ cultures of mammary glands, hepatocyte growth factor (HGF, scatter fac tor) promoted branching of the ductal trees but inhibited the producti on of secretory proteins. Neuregulin (NRG, neu differentiation factor) stimulated lobulo-alveolar budding and the production of milk protein s. These functional effects are paralleled by the expression of the tw o factors in vivo: HGF is produced in mesenchymal cells during ductal branching in the virgin animal; NRG is expressed in the mesenchyme dur ing lobulo-alveolar development at pregnancy. The receptors of HGF and NRG (c-met, c-erbB3, and c-erbB4), which are expressed in the epithel ial cells, are not regulated. In organ culture, branching morphogenesi s and lobulo-alveolar differentiation of the mammary gland could be ab olished by blocking expression of endogenous HGF and NRG by the respec tive antisense oligonucleotides; in antisense oligonucleotide-treated glands, morphogenesis could again be induced by the addition of recomb inant HGF and NRG. We thus show that two major postnatal morphogenic p eriods of mammary gland development are dependent on sequential mesenc hymal-epithelial interactions mediated by HGF and NRG.