Search

Connective tissue growth factor (CTGF) is a matricellular protein that plays a critical role in the development of ovarian follicles. Growth differentiation factor 8 (GDF8) is mainly, but not exclusively, expressed in the mammalian musculoskeletal system and is a potent negative regulator of skeletal muscle growth. The aim of this study was to investigate the effects of GDF8 and CTGF on the regulation of cell proliferation in human granulosa cells and to examine its underlying molecular determinants. Using dual inhibition approaches (inhibitors and small interfering RNAs), we have demonstrated that GDF8 induces the up-regulation of CTGF expression through the activin receptor-like kinase (ALK)4/5-mediated SMAD2/3-dependent signaling pathways. In addition, the increase in CTGF expression contributes to the GDF8-induced suppressive effect on granulosa cell proliferation. Our findings suggest that GDF8 and CTGF may play critical roles in the regulation of proliferative events in human granulosa cells., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Ovarian cancer may be the most frequently lethal gynaecological malignancy but the heterogeneous nature of the disease and the advanced stage at which it is usually diagnosed, have contributed to the paucity of information relating to its aetiology and pathogenesis. Members of the TGF-β superfamily, estrogen and NFκB have all been implicated in the development and progression of cancers from a wide range of tissues. In the ovary, TGF-β superfamily members and estrogen play key roles in maintaining normal function. To date, little is known about the capacity of NFκB to influence normal ovarian function except that it is ubiquitously expressed. In this review we will highlight the roles that inhibin/activin, estrogen and NFκB, have been attributed within carcinogenesis and examine the potential for crosstalk between these pathways in ovarian cancer pathogenesis., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Granulosa cells are the main ovarian source of inhibins, activins and activin-binding protein (follistatin) while germ (oogonia, oocytes) and somatic (theca, granulosa, luteal) cells express activin receptors, signaling components and inhibin co-receptor (betaglycan). Activins are implicated in various intra-ovarian roles including germ cell survival and primordial follicle assembly; follicle growth from preantral to mid-antral stages; suppression of thecal androgen production; promotion of granulosa cell proliferation, FSHR and CYP19A1 expression; enhancement of oocyte developmental competence; retardation of follicle luteinization and/or atresia and involvement in luteolysis. Inhibins (primarily inhibin A) are produced in greatest amounts by preovulatory follicles (and corpus luteum in primates) and suppress FSH secretion through endocrine negative feedback. Together with follistatin, inhibins act locally to oppose auto-/paracrine activin (and BMP) signaling thus modulating many of the above processes. The balance between activin-inhibin shifts during follicle development with activin signalling prevailing at earlier stages but declining as inhibin and betaglycan expression rise., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

The transforming growth factor-beta (TGF-β) superfamily of ligands have been recognized as important signals in vertebrate embryonic development from the blastula stage to adulthood. In addition to roles in early development, TGF-β superfamily ligands, and particularly activin family ligands, are involved in specification, differentiation, and proliferation of multiple organ systems, including the pancreas. More recently, research has suggested that activin family ligands, binding proteins, receptors, and Smad signal transducers and modulators are involved in regulating adult pancreatic function and maintaining pancreatic islet homeostasis in the adult. This article will focus on outlining common themes in activin family regulation of embryonic pancreatic development and adult pancreatic homeostasis, particularly in activin family involvement in setting and maintaining populations of islet cells such as β-cells., (Copyright © 2012. Published by Elsevier Ireland Ltd.)

Activin and inhibin, two closely related protein hormones, are members of the transforming growth factor beta (TGF beta) superfamily of growth factors. Activin and TGF beta have been associated with mouse mammary gland development and human breast carcinogenesis. TGF beta expression in the mammary gland has been previously described, and was found to be expressed in nonparous tissue and during pregnancy, down-regulated during lactation, and then up-regulated during involution. The expression pattern of activin subunits, receptors and cytoplasmic signaling molecules has not been thoroughly described in post-natal mammary gland development. We hypothesize that activin signaling components are dynamically regulated during mammary gland development, thereby permitting activin to have distinct temporal growth regulatory actions on this tissue. To examine the activin signal transduction system in the mammary gland, tissue from CD1 female mice was dissected from nonparous, lactating day 1, 10, and 20 and post-weaning day 4 animals. The expression of the activin receptors (ActRIIA, ActRIIB and ActRIB), the inhibin co-receptor (betaglycan), and ligand subunit (alpha, beta A and beta B), mRNA was measured by semi-quantitative RT-PCR in these tissues. In addition, the cellular compartmentalization of the activin signaling proteins, including the cytoplasmic signaling co-activators, Smads 2, 3 and 4, were examined by immunohistochemistry. Generally, mRNA abundance of activin signaling components was greatest in the nonparous tissue, and then decreased, whereas protein immunoreactivity for activin signaling components increased during lactation and decreased during involution. The alpha-subunit protein was detected in nonparous and lactating day 1 tissue only. Importantly, Smad 3, but not Smad 2, was detected in epithelial cell nuclei during all time points examined, indicating that activin signaling is mediated by Smad 3 at these times. These findings suggest that activin's growth regulatory role during lactation may be distinguished from that of TGF beta during post-natal mammary development. Future studies will focus on determining the exact role this ligand plays in mammary tissue differentiation and neoplasia.

Peripheral endocrine hormones and local paracrine and autocrine factors contribute, in a coordinated fashion, to the processes of recruitment, development or atresia, selection and ovulation of follicles. Among the local ovarian factors, there is growing evidence from genetic and experimental data that many members of the transforming growth factor (TGFbeta) superfamily have a biological role to play in folliculogenesis. These members include activin, inhibin, TGFbeta, BMP, GDF9 and perhaps MIS. In this review, we discuss the potential roles of the TGFbeta superfamily members, in particular activin, during folliculogenesis. Since the actions of these factors are determined by ligand availability, receptor expression and modulation of their signal transduction pathways, we also collate information on the expression of their signalling components in the follicle. We conclude that the TGFbeta superfamily signalling pathways, in particular activin's pathway, reside in the ovary. Furthermore, follistatin and beta-glycan-components of the accessory binding protein system that modifies activin action-are also present in follicles. In the post-natal rat ovary, the changes in receptor/Smad expression coincide with granulosa cell proliferation and antrum formation. We hypothesise that these pathway components are expressed in a temporal and cell-specific manner to meet the changing demands of cells during follicular development. The analysis of the components of the signal transduction pathways of the TGFbeta family members in populations of defined follicles and the identification of activated pathways in individually stimulated follicles should help clarify the roles of the TGFbeta members in folliculogenesis.

Granulosa cell tumours (GCT) of the ovary arise from granulosa cells of the ovary on morphological, biochemical and molecular criteria. In order to understand the molecular pathogenesis of these tumours better we have sought to define their molecular phenotype, to identify activating mutations of the FSH-signalling pathway, to characterise their estrogen receptor expression and to explore the hypothesis that GCT may be resistant to inhibin. The pattern of gene expression observed in GCT suggests a phenotype which is similar to that of late preovulatory granulosa cells which would be consistent with activation of the FSH receptor signalling pathway, however, there is no evidence for activating mutations of either the FSH receptor or the associated trimeric G-proteins. Estrogen receptor beta is abundantly expressed in GCT. The various subunits and isoforms of the activin-inhibin receptor are expressed in GCT. These observations provide a basis for future studies of GCT, including further characterisation of signalling pathways known to be important in the regulation of granulosa cell growth and differentiation.

The identification and characterization of components of the transforming growth factor beta (TGFbeta) signalling pathway are proceeding at a very fast pace. To illustrate a number of our activities in this field, we first summarize our work aiming at the selection from a large collection of single residue substitution mutants of two activin A polypeptides in which D27 and K102, respectively, have been modified. This work has highlighted the importance of K102 and its positive charge for binding to activin type II receptors. Activin K102E, which did not bind to high-affinity receptor complexes, may be a valuable beta chain, when incorporated in recombinant inhibin to unambiguously detect novel inhibin binding sites at the cell surface. We then illustrate how Smad5 knockout mice and an overexpression approach with a truncated TGFbeta type II receptor in the mouse embryo can contribute to the identification of a novel TGFbeta-->TbetaRII/ALK1-->Smad5 pathway in endothelial cells in the embryo proper and the yolk sac vasculature. We conclude with a summary of our results with a Smad-interacting transcriptional repressor but focus on its biological significance in the vertebrate embryo.

Activin signal transduction is regulated through multiple mechanisms. We have identified novel regulatory proteins that control activin functions either intracellularly or extracellularly. As intracellular molecules, PSD-95/Dlg/ZO-1 (PDZ) proteins that specifically associate with activin type II receptors (ActRIIs) were identified. We have named the molecules as activin receptor-interacting proteins (ARIPs). ARIP1 has two WW domains and five PDZ domains, associates not only with ActRIIs but also with Smads, and controls activin functions intracellularly in neuronal cells. Another ARIP we have found has only one PDZ domain, and is likely to be involved in intracellular trafficking and sorting of activin receptor complexes in the cell. As an extracellular regulatory protein, we have identified a novel follistatin-like protein, named follistatin-related gene (FLRG). Like follistatins, FLRG binds activins and bone morphogenetic proteins (BMPs) and controls their functions extracellularly. The mode of association of follistatin and FLRG with activins and their expression patterns are different, suggesting the distinct functions of follistatin and FLRG in vivo.