Notch4 and Wnt-1 proteins function to regulate branching morphogenesis of mammary epithelial cells in an opposing fashion

Dev Biol. 1998 Apr 15;196(2):204-17. doi: 10.1006/dbio.1998.8863.


Elongation and branching of epithelial ducts is a crucial event during the development of the mammary gland. Branching morphogenesis of the mouse mammary epithelial TAC-2 cell line was used as an assay to examine the role of Wnt, HGF, TGF-beta, and the Notch receptors in branching morphogenesis. Wnt-1 was found to induce the elongation and branching of epithelial tubules, like HGF and TGF-beta 2, and to strongly cooperate with either HGF or TGF-beta 2 in this activity. Wnt-1 displayed morphogenetic activity in TAC-2 cells as it induced branching even under conditions that normally promote cyst formation. The Notch4(int-3) mammary oncoprotein, an activated form of the Notch4 receptor, inhibited the branching morphogenesis normally induced by HGF and TGF-beta 2. The minimal domain within the Notch4(int-3) protein required to inhibit morphogenesis consists of the CBF-1 interaction domain and the cdc10 repeat domain. Coexpression of Wnt-1 and Notch4(int-3) demonstrates that Wnt-1 can overcome the Notch-mediated inhibition of branching morphogenesis. These data suggest that Wnt and Notch signaling may play opposite roles in mammary gland development, a finding consistent with the convergence of the wingless and Notch signaling pathways found in Drosophila.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Division
  • Cell Line
  • Cholera Toxin / pharmacology
  • Collagen
  • Epithelial Cells / cytology*
  • Hepatocyte Growth Factor / pharmacology
  • Hydrocortisone / pharmacology
  • Mammary Glands, Animal / cytology
  • Mammary Glands, Animal / growth & development*
  • Mice
  • Molecular Sequence Data
  • Morphogenesis
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / physiology*
  • Receptor, Notch4
  • Receptors, Cell Surface*
  • Receptors, Notch
  • Recombinant Fusion Proteins / analysis
  • Sequence Deletion
  • Signal Transduction
  • Transforming Growth Factor beta / pharmacology
  • Wnt Proteins
  • Wnt1 Protein
  • Zebrafish Proteins*


  • NOTCH4 protein, human
  • Proto-Oncogene Proteins
  • Receptor, Notch4
  • Receptors, Cell Surface
  • Receptors, Notch
  • Recombinant Fusion Proteins
  • Transforming Growth Factor beta
  • Wnt Proteins
  • Wnt1 Protein
  • Wnt1 protein, mouse
  • Zebrafish Proteins
  • Hepatocyte Growth Factor
  • Collagen
  • Cholera Toxin
  • Hydrocortisone