期刊
DEVELOPMENTAL BIOLOGY
卷 306, 期 1, 页码 193-207出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ydbio.2007.03.013
关键词
MAPK(ERK1,2); kinetics; mammary; branching; morphogenesis; TGF alpha; FGF7
资金
- NCI NIH HHS [R01 CA057621-14, R01 CA057621-15, R01 CA057621-12, CA57621, R01 CA057621-11, R01 CA057621, R01 CA057621-13] Funding Source: Medline
- NHLBI NIH HHS [T32 HL007731, HL-007731] Funding Source: Medline
- NIEHS NIH HHS [ES012801, U01 ES012801, U01 ES012801-04S3] Funding Source: Medline
Transforming growth factor-a (TGF alpha) 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 TGF alpha, 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 TGF alpha, 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 TGF alpha indicated that the FGF7-induced MAPK(ERK1,2) signaling and associated phenotypes were dominant: FGF7 may prevent branching by suppression of two necessary TGF alpha-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. (C) 2007 Published by Elsevier Inc.
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