Targeted Disruption of Mapk14 (p38MAPKα) in Granulosa Cells and Cumulus Cells Causes Cell-Specific Changes in Gene Expression Profiles that Rescue Cell-Oocyte Complex Expansion and Maintain Fertility

Abstract

MAPK14 (p38MAPK) is critical for FSH and prostaglandin E (PGE)2 signaling cascades in granulosa cells (GCs) and cumulus cell-oocytecomplexes(COCs)inculture,indicatingthatthiskinasemightimpactfolliculardevelopmentandCOCexpansioninvivo. BecauseMapk14knockoutmiceareembryoniclethal,wegeneratedGCspecificMapk14knockoutmice(Mapk14gc / )bymating Mapk14 fl/fl andCyp19a1-Cremice.Unexpectedly,theMapk14gc / femalemicewerefertile.Analysesofgeneexpressionpatterns showed that amphiregulin (Areg) and epiregulin (Ereg), two key regulators of ovulation and COC expansion, were up-regulated in the GCs but down-regulated in cumulus cells of the mutant mice in vivo. COCs from the mutant mice expanded and expressed matrix-relatedgenes,ifculturedwithAREG,butnotwhenculturedwithforskolinorPGE2,thelatterbeingakeyfactorregulating MAPK14 activity in cumulus cells. Conversely, when GCs from the Mapk14gc / mice were cultured with forskolin, they produced