Notch4 and Wnt-1 proteins function to regulate branching morphogenesis of mammary epithelial cells in an opposing fashion.
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.
Uyttendaele
H
H
Department of Pathology, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.
Soriano
J V
JV
Montesano
R
R
Kitajewski
J
J
D000595:Amino Acid Sequence; D000818:Animals; D002455:Cell Division; D002460:Cell Line; D002772:Cholera Toxin / Q000494:pharmacology; D003094:Collagen; D004847:Epithelial Cells / Q000166:cytology*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006854:Hydrocortisone / Q000494:pharmacology; D008321:Mammary Glands, Animal / Q000166:cytology / Q000254:growth & development*; D051379:Mice; D008969:Molecular Sequence Data; D009024:Morphogenesis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D000074562:Receptor, Notch4; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins / Q000032:analysis; D017384:Sequence Deletion; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D051153:Wnt Proteins; D051155:Wnt1 Protein; D029961:Zebrafish Proteins
C106075:NOTCH4 protein, human; D011518:Proto-Oncogene Proteins; D000074562:Receptor, Notch4; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D029961:Zebrafish Proteins; D017228:Hepatocyte Growth Factor; D003094:Collagen; D002772:Cholera Toxin; D006854:Hydrocortisone