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

摘要

Transforminggrowthfactor-α(TGFα)andfibroblastgrowthfactor-7(FGF7)exhibitdistinctexpressionpatternsinthemammarygland.Bothfactorssignalthroughmitogen-activatedkinase/extracellularregulatedkinase-1,2(MAPKsupERK1,2/sup);however,theiruniqueand/orcombinedcontributionstomammarymorphogenesishavenotbeenexamined.Inexvivomammaryexplants,weshowthatasustainedactivationofMAPKsupERK1,2/supfor1nbsp;h,inducedbyTGFα,wasnecessaryandsufficienttoinitiatebranchingmorphogenesis,whereasatransientactivation(15nbsp;min)ofMAPKsupERK1,2/sup,inducedbyFGF7,ledtogrowthwithoutbranching.UnlikeTGFα,FGF7promotedsustainedproliferationaswellasectopiclocalizationof,andincreasein,keratin-6expressingcells.TheresponseoftheexplantstoFGF10wassimilartothattoFGF7.SimultaneousstimulationbyFGF7andTGFαindicatedthattheFGF7-inducedMAPKsupERK1,2/supsignalingandassociatedphenotypesweredominant:FGF7maypreventbranchingbysuppressionoftwonecessaryTGFα-inducedmorphogeneticeffectors,matrixmetalloproteinase-3(MMP-3/stromelysin-1),andfibronectin.Ourfindingsindicatethatexpressionofmorphogeneticeffectors,proliferation,andcell-typedecisionsduringmammaryorganoidmorphogenesisareintimatelydependentonthedurationofactivationofMAPKsupERK1,2/supactivation./p/div