| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030
 |
ABSTRACT |
|---|
 TOP ABSTRACT I. OverviewII. Interactions of the IGF-1,...III. Regulated Expression of Wnts and...IV. Genes Involved in OvulationIV. SummaryACKNOWLEDGEMENTSREFERENCES |
|---|
|
I. Overview |
|---|
|
TOPABSTRACTI. OverviewII. Interactions of the IGF-1,...III. Regulated Expression of Wnts and...IV. Genes Involved in OvulationIV. SummaryACKNOWLEDGEMENTSREFERENCES |
|---|
|
II. Interactions of the IGF-1, Estradiol, and FSH Signaling Cascades |
|---|
|
TOPABSTRACTI. OverviewII. Interactions of the IGF-1,...III. Regulated Expression of Wnts and...IV. Genes Involved in OvulationIV. SummaryACKNOWLEDGEMENTSREFERENCES |
|---|
|
The mammalian homologue of the nuclear receptor Daf12 is not yet known. However, three members of the Forkhead family have been identified in the mouse: FKHR (Foxo-1), FKHRL1 (Foxo-3), and AFX (Foxo-4) (Kaestner et al., 2000; Brunet et al., 2001). A current model of IGF-1 action indicates that phosphorylation of Forkhead by PKB (or related kinases) restricts nuclear localization of these factors (Nakae et al., 2000; Brownawell et al., 2001). This impedes transcriptional activation of specific Forkhead target genes, such as Fas ligand (FasL), an inducer of apoptosis (Brunet et al., 1999), p27KIP, an inhibitor of cell cycle progression (Medema et al., 2000) and insulin-like growth factor binding protein-1 (IGFBP-1), a presumed inhibitor of IGF-1 (Kops et al., 1999; Guidice, 2000). Recently, we have shown that FKHR, FKHRL1, and AFX are expressed in the rodent (mouse and rat) ovary in a cell-specific manner at defined stages of follicular growth and luteinization (Richards et al., in press (b)). Expression of FKHR mRNA is restricted to granulosa cells of growing follicles and is not detected in luteal cells. In contrast, FKHRL1 and AFX are highest in corpora lutea, where the PKB-related kinase, serum and glucocorticoid-induced kinase (Sgk), is also expressed in abundance (Figure 1). In addition, we have shown that FKHR expression is regulated by E, IGF-1, and the gonadotropins (Richards et al., in press (b)). E markedly increases FKHR mRNA and protein in granulosa cells of preantral follicles of the hypophysectomized (H) rat. Thus, expression of FKHR mRNA, protein, and phosphorylation are not strictly associated with follicles that are undergoing apoptosis or appear destined for atresia. Rather, FKHR is highest in granulosa cells of follicles in the hypophysectomized and estradiol-treated (HE) rats that exhibit increased proliferation (Rao et al., 1978), increased expression of cyclin D2 (Robker and Richards, 1998a,b) and increased staining for proliferator cell nuclear antigen (PCNA) (Robker and Richards, 1998a,b). FKHR is also elevated in preovulatory follicles of PMSG-treated mice, adult mice, and pregnant mice at day 22 of gestation (Figure 1). The high levels of FKHR in granulosa cells suggest a key role in promoting follicle growth. Moreover, E not only induces FKHR mRNA but also upregulates other notable components of the IGF-1 signaling system, including IGF-1Rß subunit and the glucose transporter, Glut-1 (Richards et al., in press (b)). The coordinated up-regulation of FKHR with IGF-1Rß and Glut-1 indicates further that E enhances granulosa cell function in the H rat model by regulating three different targets that control cellular energy flow, glucose metabolism, and cell survival. Because IGF-1 helps maintain high expression of estrogen receptor beta (ERß) mRNA, at least in cultured granulosa cells, E and IGF-1 comprise an autocrine regulatory system in granulosa cells that promotes cell survival and proliferation (Richards et al., in press (b)) (Figure 2).
|
The gonadotropins, as well as IGF-1, impact the phosphorylation of Forkhead proteins and thus can control their functional activity (Richards, 2001a). Specifically, we have shown previously that FSH as well as IGF-1 can impact the PI3-K pathway (Gonzalez-Robayna et al., 1999,2000). FSH, like IGF-1, stimulates phosphorylation of PKB Ser-473 that is blocked by the PI3-kinase inhibitor LY294002 but not by the protein kinase A (PKA) inhibitor, H89. Rather H89 enhances FSH and IGF-1 phosphorylation of PKB (Gonzalez-Robayna et al., 2000). FSH also induces the expression of the PKB-related kinase Sgk (Alliston et al., 1997,2000; Gonzalez-Robayna et al., 1999,2000; Burns et al., 2001). Importantly, Sgk reaches its highest levels of expression in corpora lutea in association with the increased levels of FKHRL1 and AFX (Figure 1). Based on these functions of FSH, it is not surprising that FSH stimulates the phosphorylation of FKHR at Thr-24 and Ser-256 in granulosa cells in a kinetic manner that mimics the action of IGF-1 in these same cells (Richards et al., in press (b)). Although the precise mechanism(s) by which FSH stimulates PKA-independent activation of PI3-K remains to be clearly documented, the cAMP-regulated guanine nucleotide exchange factors (cAMP-GEFs) (de Rooij et al., 1998,2000; Kawasaki et al., 1998) provide a potential new link between FSH stimulation of adenylyl cyclase and activation of PI3-K via ras-related small guanine nucleotide triphosphatases (GTPases). Whether PKB, Sgk, or other kinases specifically mediate the phosphorylation of FKHR in granulosa cells in vivo also needs to be verified (Figures 1 and 2).
|
III. Regulated Expression of Wnts and Frizzleds in the Ovary |
|---|
|
TOPABSTRACTI. OverviewII. Interactions of the IGF-1,...III. Regulated Expression of Wnts and...IV. Genes Involved in OvulationIV. SummaryACKNOWLEDGEMENTSREFERENCES |
|---|
|
Wnt-4 is also essential for the embryonic development of the ovary. Female mice null for Wnt-4 have sex-reversed ovaries that, at birth, are depleted of oocytes and contain supporting cells expressing genes characteristic of testis development such as Mullerian inhibiting substance (MIS) (Vainio et al., 1999). Since mice null for Wnt-4 die at birth, we have analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization the expression of Wnt-4 in the adult ovary. Our results show that Wnt-4 is expressed in granulosa cells of small primary follicles containing one or two layers of cells and in granulosa cells of preovulatory follicles (Figure 3) (Hsieh et al., in press). Wnt-4 expression is increased in granulosa cells by the LH surge and reaches its highest level in corpora lutea (Figure 3). Unlike the mammary gland, Wnt-4 is not a target of PR in the ovary (Hsieh et al., in press), perhaps because PRA rather than PRB plays a primary role in the follicle, whereas PRB plays a greater role in mammary tissue (Mulac-Jericevic et al., 2000; Conneely et al., 2001). Wnt-4 may control different aspects of granulosa cell and luteal cell function, depending on which Frizzled receptors are present. Although it is not yet clear which Frizzled receptor is present in primary follicles, our results show that Frizzled-1 is induced transiently by the LH surge (Hsieh et al., in press). It is localized to granulosa cells of ovulating follicles between 4–12 hours after exposure to the LH surge, just prior to ovulation. Thus, Frizzled-1 may control the expression of genes that impact the ovulation process. In contrast, Frizzled-4 is preferentially expressed at elevated levels in corpora lutea (Hsieh et al., in press). Thus, Frizzled-4 may be a receptor for Wnt-4 in this tissue (Figure 3). Mice null for Frizzled-4 also exhibit reproductive (ovarian?) defects but the exact nature of these are not yet known (J. Nathans, personal communication).
What are the functions of Wnt-4 in the adult ovary? In the embryonic gonad, the expression pattern of Wnt-4 is similar to that of DAX-1 (Swain et al., 1996; Vainio et al., 1999). More recently, overexpression of Wnt-4 in gonadal cells upregulated the expression of DAX-1 (Jordan et al., 2001), indicating that Wnt-4 may regulate DAX-1 in the ovary as well. This observation is supported by the ability of ß-catenin to enhance SF-1-stimulated transactivation of the DAX-1 promoter via Tcf/Lef promoter elements (Morohashi et al., 2001). As a co-repressor of the orphan nuclear receptor SF-1, ovarian DAX-1 may antagonize the transcriptional activation of genes that are regulated by SF-1 such as aromatase (CYP 19) (Fitzpatrick and Richards, 1994; Carlone and Richards, 1997), P450scc (CYP21) (Clemens et al., 1994; Richards, 1994), 17
-hydroxylase (CYP17) (Zang and Mellon, 1996), FSH receptor (Heckert, 2000; Levallet et al., 2001), MIS (Shen et al., 1994; Watanabe et al., 2000), and inhibin- (Ito et al., 2000). Since the expression of these genes is low in small growing follicles of immature mice and rats (Richards, 1994,2001b), it is tempting to speculate that a Wnt-4/Frizzled pathway is acting in these follicles to control Dax-1 and hence the activity of SF-1.
However, the role of Wnt-4 in the ovary appears to be complex. DAX-1 remains expressed (albeit at a lower level) in mice null for Wnt-4 (Vainio et al., 1999; Jordan et al., 2001), likely due to the potent control of DAX-1 expression by SF-1. Furthermore, only some but not all SF-1 regulated genes are elevated in the Wnt-4 null mice (Vainio et al., 1999). Mice null for DAX-1 appear to have normal ovarian function (Yu et al., 1998). Recent studies have identified and also shown that the equine ovary expresses not only SF-1 (NR-5A1) but also SF-2 (NR-5A2) (Boerboom et al., 2000). Whereas SF-1 is high in theca cells, SF-2 is highest in granulosa cells and corpora lutea. We have recently confirmed these data in the rat and mouse by RT-PCR and in situ hybridization analyses (Figure 3). Thus, although the expression of Wnt-4 in small follicles may suppress steroidogenesis at this stage of development, a critical role for DAX-1 and SF-1 or SF-2 is not entirely clear. Even more striking, Wnt-4 as well as Frizzled-4 are elevated in luteal cells that are highly steroidogenic, contain nuclear Dax-1 protein, and express SF-2 as well as SF-1 (Hsieh et al., in press) (Figure 3). Therefore, it is possible the Wnt-4/Frizzled pathway(s) operating in small follicles is (are) different than the Wnt-4/Frizzled-4 pathway that appears, but has not yet been proven, to be dominant in luteal cells. In addition, the specific downstream effectors of Wnt/Frizzled signaling may change as follicles terminally differentiate to luteal cells, thereby controlling distinct patterns of gene expression. Recent studies have shown that luteal cells exhibit elevated expression of specific kinases, including Sgk (Gonzalez-Robayna et al., 1999; Alliston et al., 2000) and a MAP kinase pathway (Maizels et al., 2001). Whether these kinases are targets (or mediators?) of Wnt/Frizzled signaling is also not known. In summary, the localization and regulation of Wnt-4, Frizzled-4, Frizzled-1 and others (Hsieh et al., in press) in the adult rodent ovary, combined with the evidence for critical roles for Wnt-4 (Vainio et al., 1999) and FGF-9 (Colvin et al., 2001) in ovary and testis development, respectively, indicate that Wnt/Frizzled signaling is important for the growth and development of ovarian follicles. The identification of these ovarian-derived regulatory molecules provides a new intraovarian regulatory network that needs to be more clearly defined.
|
IV. Genes Involved in Ovulation |
|---|
|
TOPABSTRACTI. OverviewII. Interactions of the IGF-1,...III. Regulated Expression of Wnts and...IV. Genes Involved in OvulationIV. SummaryACKNOWLEDGEMENTSREFERENCES |
|---|
A. GENES CONTROLLING CUMULUS EXPANSION
The cumulus cells surrounding the oocyte and the matrix that the cumulus cells produce prior to ovulation comprise a special functional unit. The pioneering studies of many investigators have shown that the matrix upon which the cumulus cells move is formed by at least three major components (Figure 4). These include hyaluronic acid (HA) (Hess et al., 1999; Salustri et al., 1999) and at least two HA-binding proteins, namely, tumor-necrosis factor-stimulated gene (TSG)-6 (Fulop et al., 1997; Yoshioka et al., 2000) and the serum-derived inter--inhibitor (II), also known as inter--trypsin inhibitor (ITI) or serum-derived hyaluronic acid binding protein (SHAP) (Hess et al., 1999; Sato et al., 2001; Zhou et al., 2001). HA is a high molecular weight (several million daltons), linear, unbranched glycosaminoglycan. In the ovary, HA is produced by the cumulus cells and granulosa cells adjacent to the antrum (Ochsner et al., 2001). Expansion occurs only when II enters the follicle or when serum is added to cumulus-oocyte complexes (COC) to stabilize the matrix by covalent coupling to the heavy chain (HC) of II (Hess et al., 1999; Salustri et al., 1999). The cumulus-derived matrix also contains other factors such as the proteoglycans brevican and versican (MacArthur et al., 2000).
|
I (Sato et al., 2001; Zhou et al., 2001). In each mutant mouse, the COCs within preovulatory follicles fail to undergo cumulus expansion in response to LH (Davis et al., 1999). Ovulation and cumulus expansion can be restored in the COX-2 mice by exogenous administration of PGE2 or IL-1ß (Davis et al., 2001), indicating that prostaglandins and other signaling pathways are obligatory for both events. These observations provide clear evidence that one critical site for PGE2 action in the ovulating follicle is the COC. One target of PGE2 action may be TSG-6, since expression of TSG-6 is selectively reduced in the cumulus cells (but not granulosa cells) of COX-2 and EP2 null mice (Ochsner et al., 2001). Note that TSG-6 remains selectively expressed in cumulus cells but not granulosa cells of ovulating follicles 12 hours after exposure to the LH-like molecule, human chorionic gonadotropin (hCG). These results indicate that PGE2 regulates expression of TSG-6 within the cumulus microenvironment and that TSG-6 may play some critical role in expansion of the matrix. Both TSG-6 and HA are expressed several hours prior to any visible physical expansion of the matrix (i.e., dispersion of the cumulus cells away from the oocyte). This suggests that the presence of these molecules is not sufficient for matrix formation or the movement of cumulus cells away from the oocyte (Figure 4).
The other critical component is II. Ovulation can be restored in the II-deficient (bikunin null) mice by adding serum (Sato et al., 2001; Zhou et al., 2001). II is normally excluded from follicular fluid because of its size and the avascular nature of the granulosa cell layer. It enters upon dissolution of the basal lamina during ovulation (Hess et al., 1999). II is composed of several subunits: the light chain (LC) known as bikunin, which is covalently associated with the heavy chains (HC) via a chondroitin-sulfate moiety. In the presence of HA, II undergoes a substitution reaction in which the HC (SHAP) is covalently bound to HA releasing the bikunin (Sato et al., 2001). The high degree of covalent linkage between the heavy chains and HA in the COC is unprecedented (Chen et al., 1996) and suggests that the enzyme activity controlling this process is elevated within the follicle. Indeed, studies by Larsen and colleagues have shown high activity of the HC-HA conversion process in mural granulosa cells (Chen et al., 1996). Although the enzymatic activity that catalyzes the covalent linkage to HA is essential, the biochemical identity of this converting enzyme is not yet known. Nor is it known if the enzyme is hormonally regulated in the mural granulosa cells. Such a condition would also be an important factor in controlling matrix formation.
Collectively, these observations indicate that HA and II, as well as COX-2/PGE2/EP2-induced gene products (TSG-6 and others?) are critical for COC formation or cumulus cell differentiation; lack of any one of these factors precludes expansion.
The molecular mechanisms by which LH induces expression of HAS-2, COX-2, and TSG-6 genes may be either direct via LH receptors present on cumulus cells (although this possibility is controversial) or indirect via the activation of other signaling events in the follicle (Figure 4). The latter recently has gained credence, since the previously unknown soluble oocyte-derived factor that is essential for cumulus expansion (Eppig, 1991; Salustri et al., 1999) has been provisionally identified as growth differentiation factor-9, GDF-9 (Elvin et al., 1999). In cultures of rodent granulosa cells, GDF-9 can induce the expression of both HA and COX-2 (Elvin et al., 1999). However, in vivo GDF-9 is expressed in oocytes beginning at the small primary follicle stage and continues in the oocyte after ovulation. If GDF-9 is the stimulatory factor, this raises the dilemma of why the expression of HA and COX-2 is restricted to ovulating follicles (i.e., those stimulated by the LH surge). One possible scenario that would link the obligatory requirement of LH action with that of the soluble ooctye-derived factor (i.e., GDF-9) is that this factor may need to be modified before it becomes activated. GDF-9, like other members of the TGF-ß family, is synthesized as a pro-peptide and therefore it is likely present at the surface of the oocyte-cumulus cell junctions, possibly attached to proteoglycans (Park et al., 2000) as a latent factor. Induction by LH of a specific protease (factor X) (Figure 4) may be necessary to activate and/or release GDF-9, thereby allowing it to interact with cellular receptors and induce HAS-2 and COX-2 in cumulus cells. Full resolution of the pathways by which LH induces COX-2 in granulosa cells versus cumulus cells will necessitate stage-specific knockouts of GDF-9. Knockouts of TSG-6 also are needed to convincingly show a role for this protein in cumulus expansion in vivo.
B. GENES EXPRESSED IN THECA CELLS
The specific ovulatory role of the theca cells is not well defined. Whereas matrix metalloproteinase (MMP)2 is expressed exclusively in the theca cells of preantral, preovulatory, and ovulating follicles (Lui et al., 1998), the other MMPs and their inhibitors (TIMPs) exhibit more complex expression patterns for which a function is not yet clear. Based on the regulated expression of several aldo-keto reductase enzymes in the theca cells, it is possible that they act as a protective shield to ensure that toxic levels (Richards et al., in press (a)) of compounds do not reach the granulosa cells or the oocyte at an inopportune time. These changes also may serve to protect the theca cells themselves and the ovary in general from exposure to toxic compounds.
C. LUTEINIZING HORMONE-REGULATED GENES IN GRANULOSA CELLS
The LH receptor is essential for ovulation and luteinization (Lei et al., 2001). The LH-induced transcription factors in granulosa cells include early growth regulatory factor-1 (Egr-1) (Espey et al., 2000a), CAAT enhancer binding protein beta (C/EBPß) (Sirois and Richards, 1993), and progesterone receptor (PR) (Park and Mayo, 1991; Natraj and Richards, 1993) (Figures 2 and 5). Like COX-2, each of these components of the ovulatory process is induced rapidly but is expressed only transiently, with peak levels of message and protein observed approximately 4 hours after the LH surge. Each of these mediators appears to be involved in the functional activity of granulosa cells of ovulating follicles, as revealed by knockout studies (for a review, see Richards et al., 1998,2000,in press (a)). Other transcription factors such as the activator protein-1 (AP1) family members (e.g., Fra2 and JunD) are induced rapidly by the LH surge but then remain elevated in the nondividing, terminally differentiated granulosa cells during the postovulatory luteal phase (Sharma and Richards, 2000).
|
KO mice by controlling pituitary secretion of LH (Couse and Korach, 1999; Couse et al., 1999). Two regions of the PR promoter previously thought to be involved in mediating LH induction of this gene - namely, the GC-rich region of the distal promoter and the estrogen response element (ERE)3 site of the proximal promoter (Clemens et al., 1998) - also do not seem to be required in the context of the intact promoter (S.C. Sharma and J.S. Richards, in preparation). Specifically, deletion or mutation of the GC-rich region in the context of the intact murine promoter does not alter functional activity of a luciferase reporter construct when transfected into primary cultures of granulosa cells. Likewise, deletion or mutation of the ERE3 site in the context of the intact promoter does not alter activity. Additional deletional studies and mutational studies have indicated that, in granulosa cells, the critical region of the PR promoter resides downstream relative to the putative transcriptional initiation site. In fact, the putative transcriptional start site can be deleted without affecting PR promoter activity. This critical downstream region contains one of many numerous putative cap sites scattered in the promoter, as indicated by computer-generated sequence homology searches of the PR promoter. In addition, numerous RNA transcripts are expressed in granulosa cells (Natraj and Richards, 1993). Thus, transactivation of the PR promoter in these cells appears to utilize a specific region or can use many different cap sites. Therefore, although nuclear factor Y (NF-Y), GATA, and Sp-1 binding sites have been characterized by electrophoretic mobility shift assays (EMSAs), none of these binding sites is obligatory for LH activation of PR-promoter-luciferase reporter constructs in granulosa cells (S.C. Sharma and J.S. Richards, in preparation). Thus, the key transcription factor(s) remain to be identified. Mice null for PR fail to ovulate, even when stimulated by exogenous hormones. These findings support other studies that implicated progesterone as a key player in the ovulatory process (Lydon et al., 1995; Rose et al., 1999; Pall et al., 2000). More specifically, mice null for PRA but not PRB exhibit impaired ovulation, indicating the subtype specificity of PR action in the ovulation process (Mulac-Jericevic et al., 2000; Conneely et al., 2001). Despite the failure of ovulation to occur in PRKO/PRAKO mice, the expression of COX-2, cumulus expansion, and luteinization proceed normally (Robker et al., 2000). Recently, two targets of PR action were identified. These are ADAMTS-1 (for a disintegrin and metalloproteinase with thrombospondin-like repeats) that is known as METH-1 in human (Vazquez et al., 1999; Espey et al., 2000b), and cathepsin L (Robker et al., 2000). Expression of ADAMTS-1 mRNA and protein is markedly reduced in granulosa cells of PR null mice (Figure 5).
2. ADAMTS-1
ADAMTS-1 is selectively induced by LH in granulosa cells and cumulus cells, with the peak level of mRNA and protein being produced 8–12 hours after exposure of ovaries to an ovulatory dose of hCG (a gonadotropin that is functionally analogous to LH) (Espey et al., 2000b; Robker et al., 2000). The peak in ADAMTS-1 transcription occurs after the peak of PR expression but before ovulation, which is usually observed at 14–16 hours after exposure to ovulatory hormones in mice and rats. Quite significantly, there are clear data to show that the induction of ADAMTS-1 is drastically reduced in rats when the preovulatory synthesis of progesterone is inhibited with epostane (Espey et al., 2000b) or in mice that are null for PR (Robker et al., 2000). Thus, the temporal pattern of these events indicates that ADAMTS-1 has a critical downstream role in mediating the PR-regulated ovarian activity that culminates in the rupture of a follicle. Whether or not PR acts directly or indirectly to control the expression of these two distinct proteases remains to be determined. To date, no consensus PR response element (PRRE) has been identified in the 1.6-kb ADAMTS-1 promoter and evidence for a direct effect of PR has not been observed in culture. Therefore, we propose at the moment that PR controls expression of an intermediary step that may be a specific signaling pathway that impacts transcription factor activity at the ADAMTS-1 promoter (Figure 5).
ADAMTS-1 is a multifunctional protein and, as such, could exert more than one function in the ovary. Which, if any, specifically impacts ovulation needs to be defined. Three major sites of action are likely (Figure 5). ADAMTS-1 is a potent active protease that cleaves, among other substrates, the bait region of 2-macroglobulin (Kuno et al., 1999). As an active secreted protease, it is likely to initiate one or more proteolytic cascades that account for the observed phenotype of the mice null for PR. As a protease, ADAMTS-1, like ADAMTS-4 (also expressed in the ovary), may also control the amount and the cellular location of various proteoglycans. Brevican and versican are present in follicular fluid, perlican is present in the thecal compartment, and the cell surface proteoglycans such as syndecan or glypican may be on either granulosa cells or theca cells (Ishiguro et al., 1999; MacArthur et al., 2000). Both ADAMTS-1 and ADAMTS-4 have been shown to degrade aggrecan and brevican (Kuno et al., 2000; Nakamura et al., 2000; Tortorella et al., 2000). The action of ADAMTS-1 on proteoglycans present in ovarian follicles is highly likely. By altering the local concentrations of proteoglycans, ADAMTS-1 could also regulate the activity of specific growth factors, such as GDF-9, FGF-2 and FGF-7, EGF, TGF-, or Wnts, whose activity is known to be blocked by proteoglycans (Park et al., 2000). Thus, a lack of ADAMTS-1 might prevent the activation of one or more potent bioactive factors in the follicular fluid by preventing their release from the proteoglycans.
The function for ADAMTS-1 in the follicle may be mediated by its ability to interact with specific cellular signaling molecules through disintegrin or thrombospondin motifs at the carboxy terminus of the protein (Kuno et al., 1999). Like some other ADAM proteins, ADAMTS-1 may be a signaling protein that regulates some aspect of granulosa cell function via interactions with specific cell surface G protein-coupled receptors (GPCRs), integrins, and tetraspan proteins (Bigler et al., 2000; Le Naour et al., 2000). ADAMTS-1, like thrombospondin 1 (TS-1), is also a potent antiangiogenic factor that may interact with integrins (Vazquez et al., 1999). Although TS-1 and -2 are expressed in ovarian follicles (Bagavandoss et al., 1998), the specific roles of thrombspondins and ADAMTS-1 have not been clearly delineated. Based on our limited understanding of ADAMTS-1 in mammalian cells, it is difficult to predict which of its multiple functions might be critical for impacting the process of ovulation. Mutations of ADAMTS-1, ADAMTS-4, and ADAMTS-9 genes are clearly needed to resolve this important area of ovarian cell function and ovulation (Figure 5).
3. Cathepsin L
Cathepsin L is another LH- and PR-regulated gene in the ovary that was identified by cDNA array technology (Robker et al., 2000). Cathepsin L is a member of the papain family of enzymes. It is commonly a lysosomal protease but it is also secreted from certain endocrine cells such as Sertoli cells of the testis and placental trophoblasts and from certain tumors (Ishidoh and Kominami, 1998). In the cat uterus, cathepsin L is also regulated by progesterone (Jaffe et al., 1989). The function of cathepsin L in the ovary appears to be complex. This enzyme is expressed in granulosa cells of follicles at several different stages of development in response to both FSH and LH. In addition, its expression in ovulatory follicles is impaired in PR null mice (Robker et al., 2000). A functional link between PR-regulated expression of ADAMTS-1 and cathepsin L is not immediately obvious but this issue will be clarified as more information is gained about the specific roles of these proteases in the ovulation process. Cathepsin L, like cathepsin G, may activate protease-activated receptors (PARs) (Sambrano et al., 2000).
4. PACAP and the Type-1 PACAP Receptor (PAC1)
Pituitary adenylate cyclase-activating peptide (PACAP) and PAC1 are also LH-inducible genes that have been shown to be responsive to regulation by progesterone and PR-antagonists in vivo and in vitro (Gras et al., 1999; Ko et al., 1999; Ko and Park-Sarge, 2000; Park et al., 2000). PACAP has been shown to stimulate progesterone production as well as meiotic maturation in follicle-enclosed, cumulus-enclosed oocytes (Gras et al., 1999; Ko and Park-Sarge, 2000). Thus, PACAP seemed to be a potential and attractive candidate that might act downstream of PR to regulate transcriptional activation of ADAMTS-1. However, expression of PACAP mRNA in ovaries of mice null for PR is identical to that observed in ovaries of wild-type mice, indicating that PR is not essential for LH-induced expression of PACAP (K.H. Doyle and J.S. Richards, unpublished observations). Therefore, other signaling cascades may be regulated by PR that impact the expression of ADAMTS-1 and cathepsin L.
|
IV. Summary |
|---|
|
TOPABSTRACTI. OverviewII. Interactions of the IGF-1,...III. Regulated Expression of Wnts and...IV. Genes Involved in OvulationIV. SummaryACKNOWLEDGEMENTSREFERENCES |
|---|
and ERß in the ovary as well as PR are critical for ovarian function. The identification of SF-2 is intriguing and demands that the specific roles of SF-1 and SF-2 be reanalyzed at later stages of follicular growth. The future will clearly bring more excitement and resolution to the dynamics of ovarian follicular development, ovulation, and luteinization.
|
ACKNOWLEDGEMENTS |
|---|
|
TOPABSTRACTI. OverviewII. Interactions of the IGF-1,...III. Regulated Expression of Wnts and...IV. Genes Involved in OvulationIV. SummaryACKNOWLEDGEMENTSREFERENCES |
|---|
|
REFERENCES |
|---|
|
TOPABSTRACTI. OverviewII. Interactions of the IGF-1,...III. Regulated Expression of Wnts and...IV. Genes Involved in OvulationIV. SummaryACKNOWLEDGEMENTSREFERENCES |
|---|
knockout mouse.
Endocrinology
140:
5855–5894-inhibitor binding to hyaluronan in the cumulus extracellular matrix is required for optimal ovulation and development of mouse oocytes.
Biol Reprod
61:
436–443 with FKHR.
J Biol Chem
276:
33554–33560This article has been cited by other articles:
 |
|
 |
|
  M. A. Edson, A. K. Nagaraja, and M. M. Matzuk The Mammalian Ovary from Genesis to Revelation Endocr. Rev., October 1, 2009; 30(6): 624 - 712. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Nilsson, G. Dole, and M. K Skinner Neurotrophin NT3 promotes ovarian primordial to primary follicle transition Reproduction, October 1, 2009; 138(4): 697 - 707. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Sanchez, T. Adriaenssens, S. Romero, and J. Smitz Quantification of oocyte-specific transcripts in follicle-enclosed oocytes during antral development and maturation in vitro Mol. Hum. Reprod., September 1, 2009; 15(9): 539 - 550. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Adhikari and K. Liu Molecular Mechanisms Underlying the Activation of Mammalian Primordial Follicles Endocr. Rev., August 1, 2009; 30(5): 438 - 464. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Li, J. Liu, E.-S. Park, M. Jo, and T. E. Curry Jr. The B Cell Translocation Gene (BTG) Family in the Rat Ovary: Hormonal Induction, Regulation, and Impact on Cell Cycle Kinetics Endocrinology, August 1, 2009; 150(8): 3894 - 3902. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Li and T. E. Curry Jr. Regulation and Function of Tissue Inhibitor of Metalloproteinase (TIMP) 1 and TIMP3 in Periovulatory Rat Granulosa Cells Endocrinology, August 1, 2009; 150(8): 3903 - 3912. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Santen, H. Brodie, E. R. Simpson, P. K. Siiteri, and A. Brodie History of Aromatase: Saga of an Important Biological Mediator and Therapeutic Target Endocr. Rev., June 1, 2009; 30(4): 343 - 375. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Grado-Ahuir, P. Y. Aad, G. Ranzenigo, F. Caloni, F. Cremonesi, and L. J. Spicer Microarray analysis of insulin-like growth factor-I-induced changes in messenger ribonucleic acid expression in cultured porcine granulosa cells: Possible role of insulin-like growth factor-I in angiogenesis J Anim Sci, June 1, 2009; 87(6): 1921 - 1933. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Goto, A. Iwase, T. Harata, S. Takigawa, K. Suzuki, S. Manabe, and F. Kikkawa IGF1-induced AKT phosphorylation and cell proliferation are suppressed with the increase in PTEN during luteinization in human granulosa cells Reproduction, May 1, 2009; 137(5): 835 - 842. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Priyanka, P. Jayaram, R. Sridaran, and R. Medhamurthy Genome-Wide Gene Expression Analysis Reveals a Dynamic Interplay between Luteotropic and Luteolytic Factors in the Regulation of Corpus Luteum Function in the Bonnet Monkey (Macaca radiata) Endocrinology, March 1, 2009; 150(3): 1473 - 1484. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. P. Kayampilly and K. M. J. Menon Follicle-Stimulating Hormone Inhibits Adenosine 5'-Monophosphate-Activated Protein Kinase Activation and Promotes Cell Proliferation of Primary Granulosa Cells in Culture through an Akt-Dependent Pathway Endocrinology, February 1, 2009; 150(2): 929 - 935. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kenigsberg, Y. Bentov, V. Chalifa-Caspi, G. Potashnik, R. Ofir, and O. S. Birk Gene expression microarray profiles of cumulus cells in lean and overweight-obese polycystic ovary syndrome patients Mol. Hum. Reprod., February 1, 2009; 15(2): 89 - 103. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. A McLaughlin and S. C McIver Awakening the oocyte: controlling primordial follicle development Reproduction, January 1, 2009; 137(1): 1 - 11. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Li, S. A. Pangas, C. J. Jorgez, J. M. Graff, M. Weinstein, and M. M. Matzuk Redundant Roles of SMAD2 and SMAD3 in Ovarian Granulosa Cells In Vivo Mol. Cell. Biol., December 1, 2008; 28(23): 7001 - 7011. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-Y. Fan, Z. Liu, N. Cahill, and J. S. Richards Targeted Disruption of Pten in Ovarian Granulosa Cells Enhances Ovulation and Extends the Life Span of Luteal Cells Mol. Endocrinol., September 1, 2008; 22(9): 2128 - 2140. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Kang, S. K. Lee, M.-H. Kim, J. Song, S. J. Bae, N. K. Kim, S.-H. Lee, and K. Kwack Parathyroid hormone-responsive B1 gene is associated with premature ovarian failure Hum. Reprod., June 1, 2008; 23(6): 1457 - 1465. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Sriraman, U. Eichenlaub-Ritter, J. W. Bartsch, A. Rittger, S. M. Mulders, and J. S. Richards Regulated Expression of ADAM8 (a Disintegrin and Metalloprotease Domain 8) in the Mouse Ovary: Evidence for a Regulatory Role of Luteinizing Hormone, Progesterone Receptor, and Epidermal Growth Factor-Like Growth Factors Biol Reprod, June 1, 2008; 78(6): 1038 - 1048. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Uribe, T. Zarinan, M. A. Perez-Solis, R. Gutierrez-Sagal, E. Jardon-Valadez, A. Pineiro, J. A. Dias, and A. Ulloa-Aguirre Functional and Structural Roles of Conserved Cysteine Residues in the Carboxyl-Terminal Domain of the Follicle-Stimulating Hormone Receptor in Human Embryonic Kidney 293 Cells Biol Reprod, May 1, 2008; 78(5): 869 - 882. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. R. Brown, K. D. Clark, M. Gulia, Z. Zhao, S. F. Garczynski, J. W. Crim, R. J. Suderman, and M. R. Strand An insulin-like peptide regulates egg maturation and metabolism in the mosquito Aedes aegypti PNAS, April 15, 2008; 105(15): 5716 - 5721. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Shkolnik, S. Ben-Dor, D. Galiani, A. Hourvitz, and N. Dekel Molecular characterization and bioinformatics analysis of Ncoa7B, a novel ovulation-associated and reproduction system-specific Ncoa7 isoform Reproduction, March 1, 2008; 135(3): 321 - 333. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. J Spicer, P. Y Aad, D. T Allen, S. Mazerbourg, A. H Payne, and A. J Hsueh Growth Differentiation Factor 9 (GDF9) Stimulates Proliferation and Inhibits Steroidogenesis by Bovine Theca Cells: Influence of Follicle Size on Responses to GDF9 Biol Reprod, February 1, 2008; 78(2): 243 - 253. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. D. Looyenga and G. D. Hammer Genetic Removal of Smad3 from Inhibin-Null Mice Attenuates Tumor Progression by Uncoupling Extracellular Mitogenic Signals from the Cell Cycle Machinery Mol. Endocrinol., October 1, 2007; 21(10): 2440 - 2457. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Sen, A. Bettegowda, F. Jimenez-Krassel, J. J. Ireland, and G. W. Smith Cocaine- and Amphetamine-Regulated Transcript Regulation of Follicle-Stimulating Hormone Signal Transduction in Bovine Granulosa Cells Endocrinology, September 1, 2007; 148(9): 4400 - 4410. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Lofrano-Porto, G. B. Barra, L. A. Giacomini, P. P. Nascimento, A. C. Latronico, L. A. Casulari, and F. d. A. da Rocha Neves Luteinizing Hormone Beta Mutation and Hypogonadism in Men and Women N. Engl. J. Med., August 30, 2007; 357(9): 897 - 904. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Wayne, H.-Y. Fan, X. Cheng, and J. S. Richards Follicle-Stimulating Hormone Induces Multiple Signaling Cascades: Evidence that Activation of Rous Sarcoma Oncogene, RAS, and the Epidermal Growth Factor Receptor Are Critical for Granulosa Cell Differentiation Mol. Endocrinol., August 1, 2007; 21(8): 1940 - 1957. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Andreu-Vieyra, R. Chen, and M. M. Matzuk Effects of Granulosa Cell-Specific Deletion of Rb in Inha-{alpha} Null Female Mice Endocrinology, August 1, 2007; 148(8): 3837 - 3849. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Priyanka and R. Medhamurthy Characterization of cAMP/PKA/CREB signaling cascade in the bonnet monkey corpus luteum: expressions of inhibin-{alpha} and StAR during different functional status Mol. Hum. Reprod., June 1, 2007; 13(6): 381 - 390. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Nemcova, E. Nagyova, M. Petlach, M. Tomanek, and R. Prochazka Molecular Mechanisms of Insulin-Like Growth Factor 1 Promoted Synthesis and Retention of Hyaluronic Acid in Porcine Oocyte-Cumulus Complexes Biol Reprod, June 1, 2007; 76(6): 1016 - 1024. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Neganova, H. Al-Qassab, H. Heffron, C. Selman, A. I. Choudhury, S. J. Lingard, I. Diakonov, M. Patterson, M. Ghatei, S. R. Bloom, et al. Role of Central Nervous System and Ovarian Insulin Receptor Substrate 2 Signaling in Female Reproductive Function in the Mouse Biol Reprod, June 1, 2007; 76(6): 1045 - 1053. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Visser, A. L. L. Durlinger, I. J. J. Peters, E. R. van den Heuvel, U. M. Rose, P. Kramer, F. H. de Jong, and A. P. N. Themmen Increased Oocyte Degeneration and Follicular Atresia during the Estrous Cycle in Anti-Mullerian Hormone Null Mice Endocrinology, May 1, 2007; 148(5): 2301 - 2308. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Sher, N. Yivgi-Ohana, and J. Orly Transcriptional Regulation of the Cholesterol Side Chain Cleavage Cytochrome P450 Gene (CYP11A1) Revisited: Binding of GATA, Cyclic Adenosine 3',5'-Monophosphate Response Element-Binding Protein and Activating Protein (AP)-1 Proteins to a Distal Novel Cluster of cis-Regulatory Elements Potentiates AP-2 and Steroidogenic Factor-1-Dependent Gene Expression in the Rodent Placenta and Ovary Mol. Endocrinol., April 1, 2007; 21(4): 948 - 962. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Garcia-Rudaz, F. Luna, V. Tapia, B. Kerr, L. Colgin, F. Galimi, G. A. Dissen, N. D. Rawlings, and S. R. Ojeda Fxna, a novel gene differentially expressed in the rat ovary at the time of folliculogenesis, is required for normal ovarian histogenesis Development, March 1, 2007; 134(5): 945 - 957. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Liu, S. Rajareddy, P. Reddy, K. Jagarlamudi, C. Du, Y. Shen, Y. Guo, K. Boman, E. Lundin, U. Ottander, et al. Phosphorylation and inactivation of glycogen synthase kinase-3 by soluble kit ligand in mouse oocytes during early follicular development J. Mol. Endocrinol., January 1, 2007; 38(1): 137 - 146. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. L. Pon and A. S. T. Wong Gonadotropin-Induced Apoptosis in Human Ovarian Surface Epithelial Cells Is Associated with Cyclooxygenase-2 Up-Regulation via the {beta}-Catenin/T-Cell Factor Signaling Pathway Mol. Endocrinol., December 1, 2006; 20(12): 3336 - 3350. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Andric and M. Ascoli A Delayed Gonadotropin-Dependent and Growth Factor-Mediated Activation of the Extracellular Signal-Regulated Kinase 1/2 Cascade Negatively Regulates Aromatase Expression in Granulosa Cells Mol. Endocrinol., December 1, 2006; 20(12): 3308 - 3320. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. D. Looyenga and G. D. Hammer Origin and Identity of Adrenocortical Tumors in Inhibin Knockout Mice: Implications for Cellular Plasticity in the Adrenal Cortex Mol. Endocrinol., November 1, 2006; 20(11): 2848 - 2863. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Jo and T. E. Curry Jr. Luteinizing Hormone-Induced RUNX1 Regulates the Expression of Genes in Granulosa Cells of Rat Periovulatory Follicles Mol. Endocrinol., September 1, 2006; 20(9): 2156 - 2172. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. N. Parakh, J. A. Hernandez, J. C. Grammer, J. Weck, M. Hunzicker-Dunn, A. J. Zeleznik, and J. H. Nilson Follicle-stimulating hormone/cAMP regulation of aromatase gene expression requires beta-catenin PNAS, August 15, 2006; 103(33): 12435 - 12440. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Agca, J. E Ries, S. J Kolath, J.-H. Kim, L. J Forrester, E. Antoniou, K. M Whitworth, N. Mathialagan, G. K Springer, R. S Prather, et al. Luteinization of porcine preovulatory follicles leads to systematic changes in follicular gene expression Reproduction, July 1, 2006; 132(1): 133 - 145. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Peluso Multiplicity of Progesterone's Actions and Receptors in the Mammalian Ovary Biol Reprod, July 1, 2006; 75(1): 2 - 8. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Pangas, X. Li, E. J. Robertson, and M. M. Matzuk Premature Luteinization and Cumulus Cell Defects in Ovarian-Specific Smad4 Knockout Mice Mol. Endocrinol., June 1, 2006; 20(6): 1406 - 1422. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Shimada, I. Hernandez-Gonzalez, I. Gonzalez-Robayna, and J. S. Richards Paracrine and Autocrine Regulation of Epidermal Growth Factor-Like Factors in Cumulus Oocyte Complexes and Granulosa Cells: Key Roles for Prostaglandin Synthase 2 and Progesterone Receptor Mol. Endocrinol., June 1, 2006; 20(6): 1352 - 1365. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A Hourvitz, E Gershon, J D Hennebold, S Elizur, E Maman, C Brendle, E Y Adashi, and N Dekel Ovulation-selective genes: the generation and characterization of an ovulatory-selective cDNA library. J. Endocrinol., March 1, 2006; 188(3): 531 - 548. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Liu, G. Baggerman, W. D'Hertog, P. Verleyen, L. Schoofs, and G. Wets In Silico Identification of New Secretory Peptide Genes in Drosophila melanogaster Mol. Cell. Proteomics, March 1, 2006; 5(3): 510 - 522. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. E Minge, N. K. Ryan, K. H. V. D. Hoek, R. L. Robker, and R. J. Norman Troglitazone Regulates Peroxisome Proliferator-Activated Receptors and Inducible Nitric Oxide Synthase in Murine Ovarian Macrophages Biol Reprod, January 1, 2006; 74(1): 153 - 160. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Hsieh, D. Boerboom, M. Shimada, Y. Lo, A. F. Parlow, U. F.O. Luhmann, W. Berger, and J. S. Richards Mice Null for Frizzled4 (Fzd4-/-) Are Infertile and Exhibit Impaired Corpora Lutea Formation and Function Biol Reprod, December 1, 2005; 73(6): 1135 - 1146. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. X. Donadeu and M. Ascoli The Differential Effects of the Gonadotropin Receptors on Aromatase Expression in Primary Cultures of Immature Rat Granulosa Cells Are Highly Dependent on the Density of Receptors Expressed and the Activation of the Inositol Phosphate Cascade Endocrinology, September 1, 2005; 146(9): 3907 - 3916. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. A. Tullet, V. Pocock, J. H. Steel, R. White, S. Milligan, and M. G. Parker Multiple Signaling Defects in the Absence of RIP140 Impair Both Cumulus Expansion and Follicle Rupture Endocrinology, September 1, 2005; 146(9): 4127 - 4137. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Sayasith, J. G. Lussier, and J. Sirois Role of Upstream Stimulatory Factor Phosphorylation in the Regulation of the Prostaglandin G/H Synthase-2 Promoter in Granulosa Cells J. Biol. Chem., August 12, 2005; 280(32): 28885 - 28893. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. A. Emmen, J. F. Couse, S. A. Elmore, M. M. Yates, G. E. Kissling, and K. S. Korach In Vitro Growth and Ovulation of Follicles from Ovaries of Estrogen Receptor (ER){alpha} and ER{beta} Null Mice Indicate a Role for ER{beta} in Follicular Maturation Endocrinology, June 1, 2005; 146(6): 2817 - 2826. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Youn, Y. Koo, I. Ji, and T. H. Ji An Upstream Initiator-Like Element Suppresses Transcription of the Rat Luteinizing Hormone Receptor Gene Mol. Endocrinol., May 1, 2005; 19(5): 1318 - 1328. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Greenaway, P. A. Gentry, J.-J. Feige, J. LaMarre, and J. J. Petrik Thrombospondin and Vascular Endothelial Growth Factor Are Cyclically Expressed in an Inverse Pattern During Bovine Ovarian Follicle Development Biol Reprod, May 1, 2005; 72(5): 1071 - 1078. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Ivanova, K. M. Dobrzycka, S. Jiang, K. Michaelis, R. Meyer, K. Kang, B. Adkins, O. A. Barski, S. Zubairy, J. Divisova, et al. Scaffold Attachment Factor B1 Functions in Development, Growth, and Reproduction Mol. Cell. Biol., April 15, 2005; 25(8): 2995 - 3006. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. L. Pon, N. Auersperg, and A. S. T. Wong Gonadotropins Regulate N-cadherin-mediated Human Ovarian Surface Epithelial Cell Survival at Both Post-translational and Transcriptional Levels through a Cyclic AMP/Protein Kinase A Pathway J. Biol. Chem., April 15, 2005; 280(15): 15438 - 15448. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Bastida, A. Cremades, M. T. Castells, A. J. Lopez-Contreras, C. Lopez-Garcia, F. Tejada, and R. Penafiel Influence of Ovarian Ornithine Decarboxylase in Folliculogenesis and Luteinization Endocrinology, February 1, 2005; 146(2): 666 - 674. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Ashkenazi, X. Cao, S. Motola, M. Popliker, M. Conti, and A. Tsafriri Epidermal Growth Factor Family Members: Endogenous Mediators of the Ovulatory Response Endocrinology, January 1, 2005; 146(1): 77 - 84. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Ma, Y. Dong, M. M. Matzuk, and T. R. Kumar Targeted disruption of luteinizing hormone {beta}-subunit leads to hypogonadism, defects in gonadal steroidogenesis, and infertility PNAS, December 7, 2004; 101(49): 17294 - 17299. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Yang, J. Wang, Y. Shen, and S. K. Roy Developmental Expression of Estrogen Receptor (ER) {alpha} and ER{beta} in the Hamster Ovary: Regulation by Follicle-Stimulating Hormone Endocrinology, December 1, 2004; 145(12): 5757 - 5766. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Sanfins, C. E. Plancha, E. W. Overstrom, and D. F. Albertini Meiotic spindle morphogenesis in in vivo and in vitro matured mouse oocytes: insights into the relationship between nuclear and cytoplasmic quality Hum. Reprod., December 1, 2004; 19(12): 2889 - 2899. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Jo, M. C. Gieske, C. E. Payne, S. E. Wheeler-Price, J. B. Gieske, I. V. Ignatius, T. E. Curry Jr., and C. Ko Development and Application of a Rat Ovarian Gene Expression Database Endocrinology, November 1, 2004; 145(11): 5384 - 5396. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A.C.O. Evans, J.L.H. Ireland, M.E. Winn, P. Lonergan, G.W. Smith, P.M. Coussens, and J.J. Ireland Identification of Genes Involved in Apoptosis and Dominant Follicle Development During Follicular Waves in Cattle Biol Reprod, May 1, 2004; 70(5): 1475 - 1484. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. K. Campbell, E. E. Telfer, R. Webb, and D. T. Baird Evidence of a Role for Follicle-Stimulating Hormone in Controlling the Rate of Preantral Follicle Development in Sheep Endocrinology, April 1, 2004; 145(4): 1870 - 1879. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Wu, K. H. Van der Hoek, N. K. Ryan, R. J. Norman, and R. L. Robker Macrophage contributions to ovarian function Hum. Reprod. Update, March 1, 2004; 10(2): 119 - 133. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Russell, K. M. H. Doyle, S. A. Ochsner, J. D. Sandy, and J. S. Richards Processing and Localization of ADAMTS-1 and Proteolytic Cleavage of Versican during Cumulus Matrix Expansion and Ovulation J. Biol. Chem., October 24, 2003; 278(43): 42330 - 42339. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. H. Burns, G. E. Owens, S. C. Ogbonna, J. H. Nilson, and M. M. Matzuk Expression Profiling Analyses of Gonadotropin Responses and Tumor Development in the Absence of Inhibins Endocrinology, October 1, 2003; 144(10): 4492 - 4507. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Hsieh, S. M. Mulders, R. R. Friis, A. Dharmarajan, and J. S. Richards Expression and Localization of Secreted Frizzled-Related Protein-4 in the Rodent Ovary: Evidence for Selective Up-Regulation in Luteinized Granulosa Cells Endocrinology, October 1, 2003; 144(10): 4597 - 4606. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Marchal, M. Caillaud, A. Martoriati, N. Gerard, P. Mermillod, and G. Goudet Effect of Growth Hormone (GH) on In Vitro Nuclear and Cytoplasmic Oocyte Maturation, Cumulus Expansion, Hyaluronan Synthases, and Connexins 32 and 43 Expression, and GH Receptor Messenger RNA Expression in Equine and Porcine Species Biol Reprod, September 1, 2003; 69(3): 1013 - 1022. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. T. Budnik, B. Brunswig-Spickenheier, and A. K. Mukhopadhyay Lysophosphatidic Acid Signals through Mitogen-Activated Protein Kinase-Extracellular Signal Regulated Kinase in Ovarian Theca Cells Expressing the LPA1/edg2-Receptor: Involvement of a Nonclassical Pathway? Mol. Endocrinol., August 1, 2003; 17(8): 1593 - 1606. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. E. Falender, R. Lanz, D. Malenfant, L. Belanger, and J. S. Richards Differential Expression of Steroidogenic Factor-1 and FTF/LRH-1 in the Rodent Ovary Endocrinology, August 1, 2003; 144(8): 3598 - 3610. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. M. Gummow, J. N. Winnay, and G. D. Hammer Convergence of Wnt Signaling and Steroidogenic Factor-1 (SF-1) on Transcription of the Rat Inhibin {alpha} Gene J. Biol. Chem., July 11, 2003; 278(29): 26572 - 26579. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-Y. Park, F. Richard, S.-Y. Chun, J.-H. Park, E. Law, K. Horner, S-L C. Jin, and M. Conti Phosphodiesterase Regulation Is Critical for the Differentiation and Pattern of Gene Expression in Granulosa Cells of the Ovarian Follicle Mol. Endocrinol., June 1, 2003; 17(6): 1117 - 1130. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Jabara, L. K. Christenson, C. Y. Wang, J. M. McAllister, N. B. Javitt, A. Dunaif, and J. F. Strauss III Stromal Cells of the Human Postmenopausal Ovary Display a Distinctive Biochemical and Molecular Phenotype J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 484 - 492. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. L. Espey and J. S. Richards Temporal and Spatial Patterns of Ovarian Gene Transcription Following an Ovulatory Dose of Gonadotropin in the Rat Biol Reprod, December 1, 2002; 67(6): 1662 - 1670. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
