Neu differentiation factor/heregulin induction by hepatocyte and keratinocyte growth factors

Hepatocyte growth-factor (HGF) is a potent, widely produced, pleiotropic me diator of mesenchymal-epithelial interaction. In a study of changes in gene expression initiated by HGF in Balb/MK keratinocytes, we observed the indu ction of Neu-differentiation factor (NDF) mRNA (also known as heregulin, or HRG). Further characterization of the regulation of NDF expression in Balb /MK keratinocytes revealed potent induction by keratinocyte growth factor ( KGF) and epidermal growth factor (EGF), but not by HGF/NK2, an alternative HGF isoform with motogenic but not mitogenic or morphogenic activities. Sus tained treatment (8 h) of Balb/MK cells with KGF stimulated secretion of ma ture NDF protein into the culture medium, and Balb/MK cells treated with pu rified recombinant NDF protein showed increased DNA synthesis. We also foun d evidence of NDF induction in two models of tissue repair in mice: in full -thickness skin wounds, following locally increased KGF production, and in kidney after partial hepatectomy, following elevation of circulating HGF le vels. These results reveal that mesenchymally-derived HGF and KGF can activ ate autocrine NDF signaling in their epithelial targets, and suggest that t his mechanism contributes to the coordination of stages of wound repair, an d possibly development, where these growth factors act in concert to direct epithelial proliferation, morphogenesis and differentiation.