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Regular Article |
a Fertility Team, SAC 2.02, Novo Nordisk A/S, 2820 Gentofte, Denmark
b Department of Anatomy and Physiology, Royal Veterinary and Agricultural University, 1870 Frederiksberg C, Denmark
c BioImage A/S, 2860 Søborg, Denmark
d Institute of Animal Physiology and Genetics, Academy of Sciences of the Czech Republic, 277 21 Libechov, Czech Republic
e Pharmacology, Health Care Discovery, Novo Nordisk A/S, 2760 Måløv, Denmark
f Research Laboratories, Schering AG, Berlin, Germany
The sterol 4,4-dimethyl-5-cholesta-8,14,24-trien-3-ol (follicular fluid meiosis-activating sterol [FF-MAS]) isolated from human follicular fluid induces resumption of meiosis in mouse oocytes cultured in vitro. The purpose of this study was to examine the hypothesis that differential signal transduction mechanisms exist for FF-MAS-induced and spontaneous in vitro resumption of meiosis in mouse oocytes. Mouse oocytes were dissected from ovaries originating from mice primed with FSH 48 h before oocyte collection. Mechanically denuded germinal vesicle (GV) oocytes were in vitro matured in medium supplemented with hypoxanthine and FF-MAS or allowed to mature spontaneously; both groups were exposed to individual compounds known to inhibit specific targets in the cell. After 20–22 h of in vitro maturation, resumption of meiosis was assessed as the frequency of oocytes in GV breakdown (GVBD) stage. Pertussis toxin (2.5 µg/ml) did not influence resumption of meiosis in either group. Dibutyryl cyclic GMP (320 µM) inhibited FF-MAS-induced GVBD, but not spontaneous GVBD, whereas the subtype 5 phosphodiesterase-inhibitor zaprinast (50 µM) inhibited GVBD in both groups. Microinjection of the catalytic subunit of cAMP-dependent protein kinase into oocytes inhibited spontaneous GVBD, but not FF-MAS-induced GVBD. An inhibitor of cytoplasmic polyadenylation, cordycepin (80 µM), inhibited or retarded spontaneous GVBD to a further extent than it did FF-MAS-induced GVBD. Spontaneous GVBD was more sensitive to the histone H1 kinase-inhibitor olomoucine (250 µM) than was FF-MAS-induced GVBD. Addition of the mitogen-activated protein kinase (MAPK)-inhibitor PD 98059 (50 µM), phospholipase C-inhibitor U-73122 (10 µM), p21ras-inhibitor lovastatine (250 µM), and the src-like kinase inhibitor PP2 (20 µg/ml) inhibited FF-MAS-induced GVBD, but not spontaneous GVBD. Both MAPKs, extracellular regulated kinase (ERK) 1 and ERK2, were phosphorylated under FF-MAS-induced meiotic resumption, in contrast to spontaneous meiotic resumption, in which ERK1 and ERK2 phosphorylation occurred 2 h after GVBD. In the present study, we show that FF-MAS acts through an MAPK-dependent pathway, and we suggest that src-like kinase, p21ras, and phosphoinositide signaling lie upstream of MAPK in the FF-MAS-activated signaling pathway. Clearly, striking pathway differences are present between spontaneous versus FF-MAS-induced meiotic resumption.
1 Supported by grant 524/98/0231 from Grant Agency of the Czech Republic to J.K.
2 Correspondence: Inger Faerge, Fertility Team, SAC 2.02, Novo Nordisk A/S, Sauntesvej 13, 2820 Gentofte, Denmark. FAX: 45 44431063; ingf{at}novonordisk.com
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