Mouse oocytes enable LH-induced maturation of the cumulus-oocyte complex via promoting EGF receptor-dependent signaling.
LH triggers the maturation of the cumulus-oocyte complex (COC), which is followed by ovulation. These ovarian follicular responses to LH are mediated by epidermal growth factor (EGF)-like growth factors produced by granulosa cells and require the participation of oocyte-derived paracrine factors. However, it is not clear how oocytes coordinate with the EGF receptor (EGFR) signaling to achieve COC maturation. The aim of the present study was to test the hypothesis that oocytes promote the expression of EGFR by cumulus cells, thus enabling them to respond to the LH-induced EGF-like peptides. Egfr mRNA and protein expression were dramatically reduced in cumulus cells of mutant mice deficient in the production of the oocyte-derived paracrine factors growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15). Moreover, microsurgical removal of oocytes from wild-type COCs dramatically reduced expression of Egfr mRNA and protein, and these levels were restored by either coculture with oocytes or treatment with recombinant GDF9 or GDF9 plus recombinant BMP15. Blocking Sma- and Mad-related protein (SMAD)2/3 phosphorylation in vitro inhibited Egfr expression in wild-type COCs and in GDF9-treated wild-type cumulus cells, and conditional deletion of Smad2 and Smad3 genes in granulosa cells in vivo resulted in the reduction of Egfr mRNA in cumulus cells. These results indicate that oocytes promote expression of Egfr in cumulus cells, and a SMAD2/3-dependent pathway is involved in this process. At least two oocyte-derived growth factors, GDF9 and BMP15, are required for EGFR expression by cumulus cells.
Su
You-Qiang
YQ
The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA.
Sugiura
Koji
K
Li
Qinglei
Q
Wigglesworth
Karen
K
Matzuk
Martin M
MM
Eppig
John J
JJ
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D055430:Bone Morphogenetic Protein 15 / Q000172:deficiency / Q000494:pharmacology; D002469:Cell Separation; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D018920:Coculture Techniques; D054885:Cumulus Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D004149:Dioxoles / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D055429:Growth Differentiation Factor 9 / Q000172:deficiency / Q000494:pharmacology; D006801:Humans; D007986:Luteinizing Hormone / Q000494:pharmacology*; D051379:Mice; D009154:Mutation / Q000235:genetics; D009865:Oocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D055430:Bone Morphogenetic Protein 15; D006063:Chorionic Gonadotropin; D004149:Dioxoles; D055429:Growth Differentiation Factor 9; D012333:RNA, Messenger; D011994:Recombinant Proteins; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D007986:Luteinizing Hormone; D066246:ErbB Receptors
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