The MAPKERK-1,2 pathway integrates distinct and antagonistic signals from TGFα and FGF7 in morphogenesis of mouse mammary epithelium

Jimmie E. Fata, Hidetoshi Mori, Andrew J. Ewald, Hui Zhang, Evelyn Yao, Zena Werb, Mina J. Bissell

Research output: Contribution to journalArticle

124 Scopus citations

Abstract

Transforming growth factor-α (TGFα) 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 (MAPKERK1,2); 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 MAPKERK1,2 for 1 h, induced by TGFα, was necessary and sufficient to initiate branching morphogenesis, whereas a transient activation (15 min) of MAPKERK1,2, induced by FGF7, led to growth without branching. Unlike TGFα, 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 TGFα indicated that the FGF7-induced MAPKERK1,2 signaling and associated phenotypes were dominant: FGF7 may prevent branching by suppression of two necessary TGFα-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 MAPKERK1,2 activation.

Original languageEnglish (US)
Pages (from-to)193-207
Number of pages15
JournalDevelopmental Biology
Volume306
Issue number1
DOIs
StatePublished - Jun 1 2007
Externally publishedYes

Keywords

  • Branching
  • FGF7
  • Kinetics
  • Mammary
  • MAPK
  • Morphogenesis
  • TGFα

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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