Epimorphin Functions as a Key Morphoregulator for Mammary Epithelial Cells

Abstract

Hepatocyte growth factor (HGF) and EGF have been reported to promote branching morphogenesis of mammary epithelial cells. We now show that it is epimorphin that is primarily responsible for this phenomenon. In vivo, epimorphin was detected in the stromal compartment but not in lumenal epithelial cells of the mammary gland; in culture, however, a subpopulation of mammary epithelial cells produced significant amounts of epimorphin. When epimorphin-expressing epithelial cell clones were cultured in collagen gels they displayed branching morphogenesis in the presence of HGF, EGF, keratinocyte growth factor, or fibroblast growth factor, a process that was inhibited by anti-epimorphin but not anti-HGF antibodies. The branch length, however, was roughly proportional to the ability of the factors to induce growth. Accordingly, epimorphin-negative epithelial cells simply grew in a cluster in response to the growth factors and failed to branch. When recombinant epimorphin was added to these collagen gels, epimorphin-negative cells underwent branching morphogenesis. The mode of action of epimorphin on morphogenesis of the gland, however, was dependent on how it was presented to the mammary cells. If epimorphin was overexpressed in epimorphin-negative epithelial cells under regulation of an inducible promoter or was allowed to coat the surface of each epithelial cell in a nonpolar fashion, the cells formed globular, alveoli-like structures with a large central lumen instead of branching ducts. This process was enhanced also by addition of HGF, EGF, or other growth factors and was inhibited by epimorphin antibodies. These results suggest that epimorphin is the primary morphogen in the mammary gland but that growth factors are necessary to achieve the appropriate cell numbers for the resulting morphogenesis to be visualized.

Involvement of epimorphin in the repair of experimental renal fibrosis in mice

“…Previous studies have shown that epimorphin has morphogenetic effects on multiple epithelial tissues, including those of skin, hair follicle, lung, intestine, mammary gland, pancreas, gall bladder and liver. [4][5][6][7][8][9][10] In addition, several investigators have reported changes in the distribution of epimorphin-positive cells in inflammatory diseases of the lung and liver. [11][12][13][14] Epimorphin not only regulates morphogenesis but also functions as a mesenchymal regulator of epithelial repair.…”

Investigation of SNARE-Mediated Membrane Trafficking in Prostate Cancer Cells

“…Isoforms of syntaxins 2 and 3, derived from alternative RNA splicing, have been identified previously (20,22,53,55). They all differ only in the COOH-terminal parts of the molecules, and our antibodies are predicted to react with all of them.…”

370 The metastasis-promoting protein, S100A4, regulates mammary branching morphogenesis

“…Collagen assay-For 3D cell cultures in 3 mg/ml collagen, primary organoids or Eph4 cell clusters were embedded in type I collagen gels as previously described (Hirai et al, 1998). In brief, the Eph4 cells were preclustered in ultra low adhesion plates (Costar, Corning Life Sciences, Lowell, MA, USA) for 24 h, and then collected by differential centrifugation.…”