The MAPK(ERK-1,2) pathway integrates distinct and antagonistic signals from TGFalpha and FGF7 in morphogenesis of mouse mammary epithelium.
Transforming growth factor-alpha (TGFalpha) and fibroblast growth factor-7 (FGF7) exhibit distinct expression patterns in the mammary gland. Both factors signal through mitogen-activated kinase/extracellular regulated kinase-1,2 (MAPK(ERK1,2)); however, their unique and/or combined contributions to mammary morphogenesis have not been examined. In ex vivo mammary explants, we show that a sustained activation of MAPK(ERK1,2) for 1 h, induced by TGFalpha, was necessary and sufficient to initiate branching morphogenesis, whereas a transient activation (15 min) of MAPK(ERK1,2), induced by FGF7, led to growth without branching. Unlike TGFalpha, FGF7 promoted sustained proliferation as well as ectopic localization of, and increase in, keratin-6 expressing cells. The response of the explants to FGF10 was similar to that to FGF7. Simultaneous stimulation by FGF7 and TGFalpha indicated that the FGF7-induced MAPK(ERK1,2) signaling and associated phenotypes were dominant: FGF7 may prevent branching by suppression of two necessary TGFalpha-induced morphogenetic effectors, matrix metalloproteinase-3 (MMP-3/stromelysin-1), and fibronectin. Our findings indicate that expression of morphogenetic effectors, proliferation, and cell-type decisions during mammary organoid morphogenesis are intimately dependent on the duration of activation of MAPK(ERK1,2) activation.
Fata
Jimmie E
JE
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. jefata@lbl.gov <jefata@lbl.gov>
Mori
Hidetoshi
H
Ewald
Andrew J
AJ
Zhang
Hui
H
Yao
Evelyn
E
Werb
Zena
Z
Bissell
Mina J
MJ
D000818:Animals; D016764:Cell Polarity; D049109:Cell Proliferation; D004848:Epithelium / Q000737:chemistry / Q000254:growth & development / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D051523:Fibroblast Growth Factor 7 / Q000494:pharmacology / Q000502:physiology*; D005353:Fibronectins / Q000378:metabolism; D005782:Gels / Q000737:chemistry; D053553:Keratin-6 / Q000032:analysis / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development*; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009024:Morphogenesis / Q000187:drug effects; D009924:Organ Culture Techniques; D010766:Phosphorylation; D015398:Signal Transduction; D016211:Transforming Growth Factor alpha / Q000494:pharmacology / Q000502:physiology*
C496454:Fgf7 protein, mouse; D005353:Fibronectins; D005782:Gels; D053553:Keratin-6; D016211:Transforming Growth Factor alpha; D051523:Fibroblast Growth Factor 7; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019278:Matrix Metalloproteinase 3