Biomedical subjects

Jock K Findlay

Publications and source records attributed to Jock K Findlay.

At least 19 recordsLinked to original sources

PubMed2006

Inhibins differentially antagonize activin and bone morphogenetic protein action in a mouse adrenocortical cell line.

Inhibin, a member of the TGF-beta superfamily, has been proposed to act as an inhibitor of activin and bone morphogenetic protein (BMP) by sequestering their type II receptors in nonsignaling complexes with betaglycan. This mechanism of inhibin action was tested in a mouse adrenocortical (AC) cell line by examining the effects of inhibins A and B on cytochrome P450 17alpha-hydroxylase 17,20-lyase (Cyp17) expression and 17alpha-hydroxylase activity, measured by progesterone 17alpha-hydroxylation, in the absence and presence of activin or BMP isoforms. Cyp17 mRNA endogenously expressed by AC cells was suppressed by activins A and B and BMP-2, -6, and -7, and each ligand accordingly inhibited 17alpha-hydroxyprogesterone production (IC(50) of 0.24, 0.27, 0.4, 0.51, and 2.2 nm, respectively). Neither inhibin A nor inhibin B alone affected Cyp17 expression or 17alpha-hydroxyprogesterone production. Both inhibin A and inhibin B blocked the inhibitory actions of activins A and B in AC cells, supporting the antiactivin model of inhibin action. Inhibin A provided more potent and effective antagonism of both activins than did inhibin B, and activin A was less subject to antagonism by either inhibin than was activin B. In contrast to the major antagonism of activin by both inhibins, only inhibin A antagonized the actions of BMP-2, BMP-6, and BMP-7, whereas inhibin B was ineffective against all tested BMP isoforms except BMP-7 at high concentrations. These results provide limited support for the anti-BMP model of inhibin action and reveal that, relative to inhibin A, inhibin B essentially behaves as a selective activin antagonist in AC cells. In conclusion, inhibins A and B differentially antagonize the actions of activins and BMPs to control adrenocortical C(19) steroid production.

Activins↗

PubMed2006

The role of activins during decidualisation of human endometrium.

Decidualisation of the endometrial stroma is critical to create a specialised environment for embryo implantation and trophoblast invasion; however, the mechanisms involved are poorly understood. We have established that activin A is an important regulator of decidualisation of endometrial stromal cells in vitro. Here we describe studies that verify the physiological significance of these findings. We demonstrate that high concentrations of activin A are produced by decidualising cells in excess of the antagonists, inhibin and follistatin, thus confirming its bioavailability within the decidual environment. Furthermore, we demonstrate that all components of the activin signalling pathway (activin receptors and Smads) are expressed in decidualised cells, and identify a downstream mechanism for activin in the endometrium, through the regulation of matrix metalloproteinases (MMPs). This new knowledge is important for understanding the roles for activins and inhibins in regulating fertility.

Activins↗

PubMed2006

Complex expression patterns support potential roles for maternally derived activins in the establishment of pregnancy in mouse.

Maternal-fetal communications are critical for the establishment of pregnancy. Embryonic growth and differentiation factors produced by the oviduct and uterus play essential roles during the pre- and early post-implantation phases. Although several studies indicate roles for activin in embryonic development, gene-knockout studies have failed to identify a critical role in mammalian embryogenesis. We hypothesized that activin is produced by maternal tissues during the establishment of pregnancy, and thus maternally derived activin could compensate for the absence of embryonic activin in null homozygotes during critical developmental stages. We investigated the expression of inhibin alpha, activin betaA, and betaB subunits in the mouse oviduct and uterus during the estrous cycle and early pregnancy, and in the early conceptus. Inhibin alpha subunit was weakly expressed, while activin betaA and betaB subunits were strongly expressed in oviduct and uterus at estrous, and dramatically upregulated in the uterus on each day of pregnancy between days 3.5 and 8.5 post coitum. Prior to implantation, activin betaA and betaB subunits were immunolocalized to oviductal and uterine epithelial cells; following implantation they were expressed in the stroma, in a wave preceding decidualization. Later in pregnancy, activin betaA and betaB subunits were present in decidua basalis, trophoblast giant cells, and labyrinth zone of the developing placenta. Expression of activin betaA subunit was also detected in blastocysts and early post-implantation embryos. These data are consistent with a role for maternally derived activins in the support of the pre-implantation embryo, and during gastrulation and embryogenesis.

Activins↗

PubMed2006

TGF-beta superfamily expression and actions in the endometrium and placenta.

Transforming growth factor beta (TGFbeta) superfamily members are closely associated with tissue remodelling events and reproductive processes. This review summarises the current state of knowledge regarding the expression and actions of TGFbeta superfamily members in the uterus, during the menstrual cycle and establishment of pregnancy. TGFbetas and activin beta subunits are abundantly expressed in the endometrium, where roles in preparation events for implantation have been delineated, particularly in promoting decidualisation of endometrial stroma. These growth factors are also expressed by epithelial glands and secreted into uterine fluid, where interactions with preimplantation embryos are anticipated. Knockout models and embryo culture experiments implicate activins, TGFbetas, nodal and bone morphogenetic proteins (BMPs) in promoting pre- and post-implantation embryo development. TGFbeta superfamily members may therefore be important in the maternal support of embryo development. Following implantation, invasion of the decidua by fetal trophoblasts is tightly modulated. Activin promotes, whilst TGFbeta and macrophage inhibitory cytokine-1 (MIC-1) inhibit, trophoblast migration in vitro, suggesting the relative balance of TGFbeta superfamily members participate in modulating the extent of decidual invasion. Activins and TGFbetas have similar opposing actions in regulating placental hormone production. Inhibins and activins are produced by the placenta throughout pregnancy, and have explored as a potential markers in maternal serum for pregnancy and placental pathologies, including miscarriage, Down's syndrome and pre-eclampsia. Finally, additional roles in immunomodulation at the materno-fetal interface, and in endometrial inflammatory events associated with menstruation and repair, are discussed.

Activins↗

PubMed2006

Rodent adrenocortical cells display high affinity binding sites and proteins for inhibin A, and express components required for autocrine signalling by activins and bone morphogenetic proteins.

Inhibins are expressed in the adrenal cortex, but little is known of their binding or role in the adrenal. The aims of the present study were, first, to establish whether a mouse adrenocortical (AC) cell line expresses inhibins/activins and bone morphogenetic proteins (BMP), along with proteins required for inhibin to antagonise activin and BMP actions and, secondly, to characterise and compare inhibin binding sites and proteins in the rat adrenal gland and AC cells. AC cells were found to: (1) express mRNA for multiple BMPs (BMP-2, -3, -4, -6, -8a), growth/differentiation factors (GDF-1, -3, -5, -9), Lefty A and B, and the inhibin alpha, beta(A) and beta(B) subunits (2) secrete inhibin A and inhibin B and (3) express mRNA encoding the inhibin co-receptor, betaglycan, along with activin and BMP type I (ALK2-7) and type II (ActRII, ActRIIB, BMPRII) receptors, and binding proteins (follistatin, BAMBI, gremlin). When applied to sections of rat adrenal glands, [(125)I]inhibin A specifically bound to cells of the adrenal cortex, mainly in the zona reticularis. Scatchard analyses of in vitro [(125)I]inhibin A binding to dispersed rat adrenal cells and AC cells revealed sites of high affinity (K(d)(1) of 0.18 and 0.15 nM, respectively) and low affinity (K(d)(2) of 2.6 and 1.3 nM, respectively. Competition for [(125)I]inhibin A binding by activin A or B (30 nM) was negligible, whereas BMP-2, -6 and -7 competed for between 21 and 33% of specific inhibin A binding (IC(50) between 0.2 and 0.3 nM). Inhibin B crossreaction with inhibin A binding sites was < 8%. Multiple binding protein complexes (molecular weight ranging from 35 to > 220 kDa) were affinity labelled by [(125)I]inhibin A on both the primary rat adrenal and AC cells. The species of > 220 kDa were shown by immunoprecipitation to include betaglycan, the species of 105 kDa is consistent in size with type II receptors for activin/BMP, and that of 62 kDa co-migrates with the inhibin-follistatin complex. In summary, the results show that inhibin A binds selectively and with both high and low affinity to AC cells via multiple binding proteins, including a single betaglycan-like species. The results support the role of glycosylated betaglycan in the high affinity binding of inhibin A, but provide consistent evidence from two independent sources of adrenal cells that inhibin A interacts with several membrane proteins in addition to those currently understood to mediate the anti-activin/BMP actions of inhibin.

Activins↗

PubMed2005

Activin A and inhibin A differentially regulate human uterine matrix metalloproteinases: potential interactions during decidualization and trophoblast invasion.

Embryo implantation and trophoblast invasion are tightly regulated processes, involving sophisticated communication between maternal decidual and fetal trophoblast cells. Decidualization is a prerequisite for successful implantation and is promoted by a number of paracrine agents, including activin A. To understand the downstream mechanisms of activin-promoted decidualization, the effects of activin on matrix metalloproteinases (MMPs) (important mediators of decidualization) were investigated. Activin A stimulated endometrial production of proMMPs-2, -3, -7, -9, and active MMP-2. In contrast, inhibin A was a potent inhibitor of proMMP-2, and antagonized the effect of activin on MMPs. Activin is up-regulated with decidualization, and MMPs-2, -3, and -9 increase in parallel. Furthermore, proMMP-2 production is stimulated when decidualization is accelerated with activin, and suppressed when activin is neutralized, attenuating decidualization. These data support that activin A promotes decidualization through up-regulating MMPs. Previous in vitro evidence proposes further roles for activin and MMPs in promoting trophoblast invasion; therefore, we examined their interrelationships in early human implantation sites. MMPs-7 and -9 were produced by static cytotrophoblast subpopulations, whereas MMP-2 was strikingly up-regulated in invasive extravillous cytotrophoblasts (EVT). Maternal decidua is the primary source of activin, where a role in stimulating MMP-2 in iEVTs can be envisaged. Inhibin was absent from cytotrophoblast populations, except for a dramatic up-regulation in endovascular EVT plugs, coinciding with a down-regulation of MMP-2. This suggests that inhibin may have a role in the cessation of vascular invasion. These data support that activin, via effects on MMPs, is an important factor in the maternal-fetal dialog regulating implantation.

Activins↗

PubMed2005

Identification of novel endometrial targets for contraception.

Successful embryo implantation is a critical step in establishing pregnancy and requires appropriate preparation of the endometrium to provide a transient state of "uterine receptivity." The most essential of the molecular events determining receptivity may therefore provide potential targets for postcoital contraception. Using the mouse as a model, we identified molecules specifically regulated in the endometrium at very early implantation: these were monoclonal nonspecific suppressor factor beta (MNSFbeta), splicing factor SC35, a novel protease of the HtrA family, termed HtrA3, calcium-binding protein (CaBP)-d9k (calbindin d9k) and proprotein convertase 6 (PC6). All of these molecules were also expressed in human endometrium, with the exception of CaBP-d9k, which was represented by the functionally similar CaBP-d28k. Appropriate spatial and temporal expressions of mRNA and protein were demonstrated for all five candidate molecules in mouse and primate (human and rhesus monkey) endometrium during the menstrual cycle and early pregnancy. Functional studies in mice established that blocking production of the CaBPs and PC6 within the endometrium completely prevented implantation and thus provided proof of principle that these molecules are potential contraceptive targets.

Animals↗

PubMed2005

Effects of phytoestrogens on the ovarian and pituitary phenotypes of estrogen-deficient female aromatase knockout mice.

OBJECTIVE: Dietary phytoestrogens are promoted as alternatives to synthetic estrogens for hormone therapy, however, their effects on the reproductive axis have not been exhaustively studied in vivo. Female aromatase knockout mouse (ArKO) mice are estrogen-free, anovulatory, and have a block in folliculogenesis, hemorrhagic cysts, and development of Sertoli cells within their ovaries. The purpose of this study was to evaluate the (ArKO) mouse as a model to test the effects of phytoestrogen replacement in vivo. DESIGN: We examined the effects of phytoestrogen-supplemented diets on the reproductive organ weights, ovarian morphology, gonadotropin levels, and the transcript levels of ovarian somatic cell and steroidogenic markers of wild-type and ArKO mice. RESULTS: The genistein diet significantly increased uterine and ovarian weights of ArKO mice. The soy, and to a larger extent the genistein diet, improved ovarian morphology. Morphological Sertoli cell transformation in ArKO mice was decreased by both diets, whereas the gene expression of Sertoli cell markers was not affected. The soy diet increased both gonadotropins in both genotypes compared with those animals on the soy-free diet. The genistein diet reduced FSH levels in ArKO mice, correlating with increased ovarian inhibin subunit expression. CONCLUSION: Phytoestrogens are estrogenic in ArKO mice. Specifically, they can affect serum gonadotropin levels, and offset the development of Sertoli cells and hemorrhagic cysts within the ovaries. However, the effects on the mouse ovary depended on the type of dietary phytoestrogen. Further studies using the ArKO mouse are required to determine the effective doses and treatment regimes for phytoestrogens as endocrine modulators.

Animals↗

PubMed2004

Inhibiting uterine PC6 blocks embryo implantation: an obligatory role for a proprotein convertase in fertility.

Successful embryo implantation involves complex interactions between the embryo and the uterus and is critical in establishing pregnancy. Proprotein convertase (PC) 6 (PC6) is one of the PC endoproteases regulating protein function through posttranslational activation of precursor proteins, including growth and differentiation factors. Here we show that PC6 protein is induced in the uterine stromal cells specifically at the site of embryo attachment during early pregnancy in mice. In vivo blocking of uterine production of PC6 protein using morpholino antisense oligonucleotides in mice resulted in total inhibition of implantation, revealing a vital role for PC6 in modulating the uterus for embryo implantation. Studies in primates (rhesus monkey and human) showed a dramatic upregulation of endometrial PC6 during the phase of uterine receptivity and at implantation, particularly during a critical uterine cell differentiation process termed decidualization. Thus, the current studies have demonstrated that PC6 is an essential molecule in modulating uterine function to support the establishment of embryo implantation. Interestingly, PC6 is one of the PCs identified to be important in processing the coat protein of HIV; inhibition of PCs has been suggested to be an effective approach to reduce HIV transmission. We therefore propose the novel concept that PC6 could be a potential nonhormonal target in the female reproductive tract for dual protection for women, both in preventing pregnancy and reducing HIV infection.

Animals↗

PubMed2004

Estrogen actions on follicle formation and early follicle development.

Estradiol-17beta (E(2)) affects late follicular development, whereas primordial follicle differentiation and early activation are believed to be independent of E(2). To test this hypothesis we compared numbers of primordial and primary follicles in wild-type and E(2)-deficient, aromatase knockout (ArKO) mice, and the immunohistochemical staining or mRNA expression of Mullerian inhibiting substance (MIS), Wilms tumor 1 (WT-1), and growth differentiation factor (GDF9), which are known to effect early follicular differentiation. Proliferating cell nuclear antigen (PCNA) staining was a marker of proliferative index. The effects of E(2) replacement for 3 wk in 7-wk-old ArKO and wild-type mice on these parameters were also tested. ArKO mice had reduced numbers of primordial and primary follicles compared with wild-type mice (63%, P < 0.001 and 60%, P = 0.062, respectively). This reduction was not corrected by E(2) treatment, suggesting that E(2) affects the initial formation or activation of primordial follicles. There was a significant increase in the diameters of the oocytes in primordial follicles of ArKO mice compared with mice of the wild type. There were no differences in the immunostaining of MIS, WT-1, and PCNA in primordial and primary follicles between wild-type and ArKO mice. The only difference was as a consequence of Sertoli and Leydig cells that develop in ovaries of ArKO mice. GDF9 mRNA expression was markedly increased in ArKO ovaries. E(2) treatment restored the ovarian follicular morphology in ArKO mice, and consequently the immunostaining patterns, but had no effect on early follicle numbers. In conclusion, E(2) has a role in controlling the size of the oocyte and primordial follicle pool in mice.

Animals↗

PubMed2004

The effects of estrogen on the expression of genes underlying the differentiation of somatic cells in the murine gonad.

Estrogen (17beta-estradiol, E2)-deficient aromatase knockout (ArKO) mice develop Sertoli and Leydig cells at puberty. We hypothesized that estrogen, directly or indirectly, regulates genes responsible for somatic cell differentiation and steroidogenesis. ArKO ovaries expressed estrogen receptors alpha and beta, and LH receptor, indices of estrogen responsiveness in the ovary. Wild-type (Wt) and ArKO mice received either E2 or placebo for 3 wk, from 7-10 wk of age. E2 decreased serum FSH and LH and increased uterine weights of 10-wk-old ArKO mice. We measured mRNA expression of Sertoli cell, Sry-like HMG box protein 9 (Sox9); three upstream transcription factors, liver receptor homolog-1 (Lrh-1), steroidogenic factor 1, and dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on the X chromosome gene 1; and one downstream factor, Müllerian-inhibiting substance. Placebo-treated ArKO ovaries have increased Sox9 (15-fold; P < 0.001), Müllerian-inhibiting substance (2.9-fold), Lrh-1 (7.7-fold), and dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on the X chromosome gene 1 (12-fold) expression compared with Wt at 10 wk. Steroidogenic factor 1 was similar to Wt. Consistent with increased serum T levels and Leydig cells in their ovaries, placebo-treated ArKO ovaries had increased 17alpha-hydroxylase, 17beta-hydroxysteroid dehydrogenase type-3, and 17beta-hydroxysteroid dehydrogenase type-1 expression compared with Wt at 10 wk. E2 treatment for 3 wk improved the ovarian phenotype, decreased development of Sertoli cells, decreased the expression of Sox9, Lrh-1, and the steroidogenic enzymes in ArKO ovaries, and induced ovulation in some cases. In conclusion, the expression of the genes regulating somatic cell differentiation is directly or indirectly responsive to estrogen.

Animals↗

PubMed2004

Animal models of inhibin action.

The physiology of inhibin has been investigated using rodent and ruminant animal models in both in vitro and in vivo studies. Inhibin was originally defined as a substance that causes selective suppression of follicle-stimulating hormone (FSH) secretion by pituitary gonadotropes. Although this definition is still valid, it fails to encompass the breadth of inhibin's actions. In addition to its endocrine action on pituitary FSH secretion, inhibin has a local paracrine action in its target tissues. The inhibin alpha subunit appears to play an important role in determining whether inhibin or activin is produced in cells. More recently, transgenic and knockout mouse models have highlighted the importance of inhibin for fertility and the inhibin alpha subunit for tumor suppression. Whether inhibin exerts its effects by a direct action on the gonad or by regulating FSH secretion, it is clear that inhibin is essential for normal reproductive function. In this article, we review the rodent and ruminant models employed to investigate inhibin physiology and examine the potential of inhibin-based vaccines to enhance gonadal function.

Animals↗

PubMed2003

Regulation of the phenotype of ovarian somatic cells by estrogen.

The pathway of mammalian sex determination, and subsequent differentiation of the gonads is under the control of the sex-determining gene, Sry, on the Y chromosome. The presence of Sry leads to the formation of a testis with its complement of Sertoli and Leydig somatic cells. In the absence of Sry, an ovary develops with granulosa and theca cells. Ovarian development is said to initiate in the XX gonad as a default pathway because the XX cells do not express Sry. This review summarizes evidence supporting the view that the ovary is not entirely a default gonad. Studies of mice with deletions in both estrogen receptor (ERalphabetaKO) or aromatase (ArKO) genes have identified an important role of estrogens in maintaining differentiation and development of somatic cells in the ovary of eutherian mammals. In the absence of estrogen (ArKO) or the capacity to transduce an estrogen signal (ERalphabetaKO), the somatic cells in the ovary exhibited a male phenotype including Sertoli and Leydig cells. When ArKO mice were replaced with estrogen, the male phenotype was diminished and there was evidence of normal folliculogenesis in the ovary. It is concluded that the differentiation of somatic cells in the eutherian ovary is influenced by the sex steroid environment.

Animals↗

PubMed2003

Ovarian follicle populations of the rat express TGF-beta signalling pathways.

The transforming growth factor-beta (TGF-beta) superfamily comprises more than 40 members, classified on the basis of structural similarity. These factors elicit a diverse range of cellular responses in insects, nematodes and vertebrates, via serine/threonine kinase receptors and intracellular Smad proteins, which when activated mediate gene transcription. Some members of the superfamily, notably activin, TGF-beta, GDF-9 and the bone morphogenetic proteins have been shown to influence ovarian function. Despite these actions, TGF-beta superfamily signalling pathways and specifically those within follicle population subtypes, have been poorly characterised in the ovary. We have shown that the ovary contains type I and II receptors and Smads, which enable it to transduce signals in response to TGF-beta superfamily members. It remains to be established however, as to which follicle subtypes these pathways are active in.

Animals↗

PubMed2003

Identification and cloning of two isoforms of human high-temperature requirement factor A3 (HtrA3), characterization of its genomic structure and comparison of its tissue distribution with HtrA1 and HtrA2.

In the present study, we identified an additional member of the human high-temperature requirement factor A (HtrA) protein family, called pregnancy-related serine protease or HtrA3, which was most highly expressed in the heart and placenta. We cloned the full-length sequences of two forms (long and short) of human HtrA3 mRNA, located the gene on chromosome 4p16.1, determined its genomic structure and revealed how the two mRNA variants are produced through alternative splicing. The alternative splicing was also verified by Northern blotting. Four distinct domains were found for the long form HtrA3 protein: (i) an insulin/insulin-like growth factor binding domain, (ii) a Kazal-type S protease-inhibitor domain, (iii) a trypsin protease domain and (iv) a PDZ domain. The short form is identical to the long form except it lacks the PDZ domain. Comparison of all members of human HtrA proteins, including their isoforms, suggests that both isoforms of HtrA3 represent active serine proteases, that they may have different substrate specificities and that HtrA3 may have similar functions to HtrA1. All three HtrA family members showed very different mRNA-expression patterns in 76 human tissues, indicating a specific function for each. Interestingly, both HtrA1 and HtrA3 are highly expressed in the placenta. Identification of the tissue-specific function of each HtrA family member is clearly of importance.

Alternative Splicing↗

PubMed2003

A novel serine protease of the mammalian HtrA family is up-regulated in mouse uterus coinciding with placentation.

This paper characterizes a novel gene, previously identified as uniquely regulated at implantation in mouse uterus. We cloned its full mRNA sequence encoding a serine protease possessing an IGF-binding domain and named it pregnancy-related serine protease (PRSP). PRSP is structurally similar to mammalian HtrA1 (56% amino acid similarity). Northern analysis revealed that the expression of PRSP mRNA was low before pregnancy, but it was increased at implantation and markedly up-regulated post-implantation. In-situ hybridization localized low levels of mRNA expression to the epithelium and stroma during very early pregnancy, but high expression to the decidual cells on day 8.5, primarily at the mesometrial pole where the placenta was forming. By day 10.5, PRSP mRNA was detected in the placenta. We also cloned an alternatively spliced PRSP mRNA that is expressed at a very low level. We located PRSP gene on chromosome 5 and established its intron/exon structure, which unambiguously explains how the two mRNA variants are produced through alternative splicing. Based on PRSP protein domain structure and its unique expression during pregnancy, we propose that PRSP plays an important role in the formation/function of the placenta.

Amino Acid Sequence↗

PubMed2003

Specific and transient up-regulation of proprotein convertase 6 at the site of embryo implantation and identification of a unique transcript in mouse uterus during early pregnancy.

The present investigation was conducted to identify and characterize an mRNA that was found by RNA differential display to be uniquely regulated at the sites of embryo implantation in mouse uterus. This mRNA was upregulated at the sites of blastocyst attachment at implantation and was identified as proprotein convertase 6 (PC6). PC6 mRNA level was low in the nonpregnant and early pregnant uterus before embryo implantation commenced (before Day 4.5, vaginal plug = Day 0). During the initiation and progression of blastocyst attachment (around Day 4.5), the mRNA was dramatically upregulated only at the implantation sites. The increased transcription was maintained on Day 5.5; the mRNA level declined slightly on Day 6.5 and then fell sharply to reach the nonpregnant level around Days 8.5-10.5. Thus, the upregulation is transient and coincides with the period of embryo attachment and implantation; it is also very specific to implantation sites. In situ hybridization analysis localized the mRNA expression predominantly in the decidual cells immediately surrounding the implanting embryo at the antimesometrial pole. Additionally, multiple mRNA species resulting from alternative splicing were observed in the uterus, as previously reported in the intestine and brain, and further analysis of these transcripts identified a uterine-specific PC6 mRNA. These data lead us to suggest that PC6 plays an important role in the processes of stromal cell decidualization and embryo implantation.

Animals↗

PubMed2002

Ovarian steroid receptors and their role in ovarian function.

The steroidogenic pathway within the ovary gives rise to progestins, androgens and oestrogens, all of which act via specific nuclear receptors to regulate reproductive function and maintain fertility. The precise role of oestrogen in the ovary remains to be elucidated, hence the data presented here which arises from studies designed to resolve this issue. Oestrogens signal via two receptor subtypes ERalpha and ERbeta, both of which are present in the ovary. ERbeta, the most abundant mRNA, is primarily expressed by GC where it transduces signals from ovarian-derived and exogenous oestrogens. Specific roles for each of the ERs in the ovary have yet to be established, despite ER knockout studies indicating both are required for normal function. The ArKO mouse is a model of oestrogen insufficiency. These mice are infertile as a result of arrested folliculogenesis (at the antral stage) and a failure to ovulate. Trans/re-differentiation of somatic cells in the ovary gives rise to Sertoli cell-like and Leydig cell-like cells within abnormal follicular structures. Disruption to the balance of sex steroids in the ovary is likely to facilitate this phenotype. Future studies will focus on the regulation of somatic cell differentiation, assigning roles to individual ERs and establishing definitive targets of oestrogen action in the ovary.

Animals↗