Paracrine actions of growth differentiation factor-9 in the mammalian ovary

被引:511
作者
Elvin, JA
Clark, AT
Wang, P
Wolfman, NM
Matzuk, MM
机构
[1] Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA
[2] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA
[3] Baylor Coll Med, Dept Cell Biol, Houston, TX 77030 USA
[4] Genet Inst Inc, Cambridge, MA 02140 USA
关键词
D O I
10.1210/me.13.6.1035
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Although the transforming growth factor-beta (TGF-beta) superfamily is the largest family of secreted growth factors, surprisingly few downstream target genes in their signaling pathways have been identified. Likewise, the identities of oocyte-derived secreted factors, which regulate important oocyte-somatic cell interactions, remain largely unknown. For example, oocytes are known to secrete paracrine growth factor(s) which are necessary for cumulus expansion, induction of hyaluronic acid synthesis, and suppression of LH receptor (LHR) mRNA synthesis. Our previous studies demonstrated that absence of the TGF-beta family member, growth differentiation factor-9 (GDF-9), blocks ovarian folliculogenesis at the primary follicle stage leading to infertility. In the present study, we demonstrate that mouse GDF-9 protein is expressed in all oocytes beginning at the type 3a follicle stage including antral follicles. To explore the biological functions of GDF-9 in the later stages of folliculogenesis and cumulus expansion, we produced mature, glycosylated, recombinant mouse GDF-9 using a Chinese hamster ovary cell expression system. A granulosa cell culture system was established to determine the role of GDF-9 in the regulation of several key ovarian gene products using semiquantitative RT-PCR. We find that recombinant GDF-9 induces hyaluronan synthase 2 (HAS2), cyclooxygenase 2 (COX-2), and steroidogenic acute regulator protein (StAR) mRNA synthesis but suppresses urokinase plasminogen activator (uPA) and LHR mRNA synthesis. Consistent with the induction of StAR mRNA by GDF-9, recombinant GDF-9 increases granulosa cell progesterone synthesis in the absence of FSH. Since induction of HASP and suppression of the protease uPA in cumulus cells are key events in the production of the hyaluronic acid-rich extracellular matrix which is produced during cumulus expansion, we determined whether GDF-9 could mimic this process. Using oocytectomized cumulus cell-oocyte complexes, we show that recombinant GDF-9 induces cumulus expansion in vitro. These studies demonstrate that GDF-9 can bind to receptors on granulosa cells to regulate the expression of a number of gene products. Thus, in addition to playing a critical function as a growth and differentiation factor during early folliculogenesis, GDF-9 functions as an oocyte-secreted paracrine factor to regulate several key granulosa cell enzymes involved in cumulus expansion and maintenance of an optimal oocyte microenvironment, processes which are essential for normal ovulation, fertilization, and female reproduction.
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页码:1035 / 1048
页数:14
相关论文
共 51 条
[1]   Phosphorylation of steroidogenic acute regulatory protein (StAR) modulates its steroidogenic activity [J].
Arakane, F ;
King, SR ;
Du, Y ;
Kallen, CB ;
Walsh, LP ;
Watari, H ;
Stocco, DM ;
Strauss, JF .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (51) :32656-32662
[2]   FSH-INDUCED EXPANSION OF THE MOUSE CUMULUS-OOPHORUS INVITRO IS DEPENDENT UPON A SPECIFIC FACTOR(S) SECRETED BY THE OOCYTE [J].
BUCCIONE, R ;
VANDERHYDEN, BC ;
CARON, PJ ;
EPPIG, JJ .
DEVELOPMENTAL BIOLOGY, 1990, 138 (01) :16-25
[3]   MOUSE OOCYTES INHIBIT PLASMINOGEN-ACTIVATOR PRODUCTION BY OVARIAN CUMULUS AND GRANULOSA-CELLS [J].
CANIPARI, R ;
EPIFANO, O ;
SIRACUSA, G ;
SALUSTRI, A .
DEVELOPMENTAL BIOLOGY, 1995, 167 (01) :371-378
[4]   Characterization of oocyte and follicle development in growth differentiation factor-9-deficient mice [J].
Carabatsos, MJ ;
Elvin, J ;
Matzuk, MM ;
Albertini, DF .
DEVELOPMENTAL BIOLOGY, 1998, 204 (02) :373-384
[5]   HORMONAL AND DEVELOPMENTAL REGULATION OF THE STEROIDOGENIC ACUTE REGULATORY PROTEIN [J].
CLARK, BJ ;
SOO, SC ;
CARON, KM ;
IKEDA, Y ;
PARKER, KL ;
STOCCO, DM .
MOLECULAR ENDOCRINOLOGY, 1995, 9 (10) :1346-1355
[6]   Growth differentiation factor-9 is required during early ovarian folliculogenesis [J].
Dong, JW ;
Albertini, DF ;
Nishimori, K ;
Kumar, TR ;
Lu, NF ;
Matzuk, MM .
NATURE, 1996, 383 (6600) :531-535
[7]  
DRAPER L, 1998, 80 ANN M END SOC NEW
[8]   Identification of an inhibin receptor in gonadal tumors from inhibin α-subunit knockout mice [J].
Draper, LB ;
Matzuk, MM ;
Roberts, VJ ;
Cox, E ;
Weiss, J ;
Mather, JP ;
Woodruff, TK .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (01) :398-403
[9]   The bone morphogenetic protein 15 gene is X-linked and expressed in oocytes [J].
Dube, JL ;
Wang, P ;
Elvin, J ;
Lyons, KM ;
Celeste, AJ ;
Matzuk, MM .
MOLECULAR ENDOCRINOLOGY, 1998, 12 (12) :1809-1817
[10]   ROLE OF OVUM IN FOLLICULAR LUTENIZATION [J].
ELFOULY, MA ;
COOK, B ;
NEKOLA, M ;
NALBANDOV, AV .
ENDOCRINOLOGY, 1970, 87 (02) :288-+