EGF-like growth factors as mediators of LH action in the ovulatory follicle.
30 Jan 2004-Science (American Association for the Advancement of Science)-Vol. 303, Iss: 5658, pp 682-684
TL;DR: It is demonstrated that LH stimulation induces the transient and sequential expression of the epidermal growth factor (EGF) family members amphiregulin, epire gulin, and beta-cellulin, which are paracrine mediators that propagate the LH signal throughout the follicle.
Abstract: Before ovulation in mammals, a cascade of events resembling an inflammatory and/or tissue remodeling process is triggered by luteinizing hormone (LH) in the ovarian follicle. Many LH effects, however, are thought to be indirect because of the restricted expression of its receptor. Here, we demonstrate that LH stimulation induces the transient and sequential expression of the epidermal growth factor (EGF) family members amphiregulin, epiregulin, and beta-cellulin. Incubation of follicles with these growth factors recapitulates the morphological and biochemical events triggered by LH, including cumulus expansion and oocyte maturation. Thus, these EGF-related growth factors are paracrine mediators that propagate the LH signal throughout the follicle.
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TL;DR: The past six years have witnessed a virtual explosion in the identification of gene mutations or polymorphisms that cause or are linked to human infertility, but translation of these findings to the clinic remains slow, however, as do new methods to diagnose and treat infertile couples.
Abstract: Reproduction is required for the survival of all mammalian species, and thousands of essential 'sex' genes are conserved through evolution. Basic research helps to define these genes and the mechanisms responsible for the development, function and regulation of the male and female reproductive systems. However, many infertile couples continue to be labeled with the diagnosis of idiopathic infertility or given descriptive diagnoses that do not provide a cause for their defect. For other individuals with a known etiology, effective cures are lacking, although their infertility is often bypassed with assisted reproductive technologies (ART), some accompanied by safety or ethical concerns. Certainly, progress in the field of reproduction has been realized in the twenty-first century with advances in the understanding of the regulation of fertility, with the production of over 400 mutant mouse models with a reproductive phenotype and with the promise of regenerative gonadal stem cells. Indeed, the past six years have witnessed a virtual explosion in the identification of gene mutations or polymorphisms that cause or are linked to human infertility. Translation of these findings to the clinic remains slow, however, as do new methods to diagnose and treat infertile couples. Additionally, new approaches to contraception remain elusive. Nevertheless, the basic and clinical advances in the understanding of the molecular controls of reproduction are impressive and will ultimately improve patient care.
840 citations
Cites background from "EGF-like growth factors as mediator..."
...Marco Conti and his co-workers showed that LH induces mural granulosa cell expression of epidermal growth factor–like factors that subsequently signal to regulate cumulus expansion-related genes in concert with oocyte-secreted growth factors (for example, GDF9 and BMP15...
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TL;DR: Two major functions of the mammalian ovary are the production of germ cells (oocytes), which allow continuation of the species, and the generation of bioactive molecules, primarily steroids and progestins and peptide growth factors, which are critical for ovarian function, regulation of the hypothalamic-pituitary-ovarian axis, and development of secondary sex characteristics.
Abstract: Two major functions of the mammalian ovary are the production of germ cells (oocytes), which allow continuation of the species, and the generation of bioactive molecules, primarily steroids (mainly estrogens and progestins) and peptide growth factors, which are critical for ovarian function, regulation of the hypothalamic-pituitary-ovarian axis, and development of secondary sex characteristics. The female germline is created during embryogenesis when the precursors of primordial germ cells differentiate from somatic lineages of the embryo and take a unique route to reach the urogenital ridge. This undifferentiated gonad will differentiate along a female pathway, and the newly formed oocytes will proliferate and subsequently enter meiosis. At this point, the oocyte has two alternative fates: die, a common destiny of millions of oocytes, or be fertilized, a fate of at most approximately 100 oocytes, depending on the species. At every step from germline development and ovary formation to oogenesis and ovaria...
641 citations
Cites background from "EGF-like growth factors as mediator..."
...The effect of these EGF-like factors on cumulus expansion occurs through up-regulation of Ptgs2, Has2, and Tnfaip6 genes (344), whose products are essential for formation and stabilization of the extracellular matrix of the cumulus oophorus....
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...How then does the LH surge lead to induction of target genes in cumulus cells that are critical for cumulus expansion? Conti and colleagues (344) have shown that the LH surge causes a rapid increase in epidermal growth factor (EGF)-like family members, Areg, Ereg, and Btc (encoding amphiregulin, epiregulin, and betacellulin, respectively), specifically in mural granulosa cells of preovulatory follicles....
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...not have an effect on denuded oocytes (344, 441)....
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TL;DR: Targeted disruption of the kinases ERK1 and ERK2 in mouse granulosa cells provides in vivo evidence that these kinases are necessary for LH-induced oocyte resumption of meiosis, ovulation, and luteinization-related events.
Abstract: A surge of luteinizing hormone (LH) from the pituitary gland triggers ovulation, oocyte maturation, and luteinization for successful reproduction in mammals. Because the signaling molecules RAS and ERK1/2 (extracellular signal–regulated kinases 1 and 2) are activated by an LH surge in granulosa cells of preovulatory follicles, we disrupted Erk1/2 in mouse granulosa cells and provide in vivo evidence that these kinases are necessary for LH-induced oocyte resumption of meiosis, ovulation, and luteinization. In addition, biochemical analyses and selected disruption of the Cebpb gene in granulosa cells demonstrate that C/EBPβ (CCAAT/Enhancer-binding protein–β) is a critical downstream mediator of ERK1/2 activation. Thus, ERK1/2 and C/EBPβ constitute an in vivo LH-regulated signaling pathway that controls ovulation- and luteinization-related events.
547 citations
TL;DR: The current understanding of additional signaling pathways and factors capable of regulating/modulating steroid hormone biosynthesis, and in many cases steroidogenic acute regulatory protein expression, are discussed in this review.
Abstract: Steroid hormone biosynthesis in steroidogenic cells is regulated through trophic hormone activation of protein kinase A (PKA) signaling pathways. However, many examples of the regulation of steroid synthesis via pathways other than the PKA pathway have been documented. In some cases these pathways act independently of PKA activation whereas in other cases, they act synergistically with it. The current understanding of additional signaling pathways and factors, such as the protein kinase C pathway, arachidonic acid metabolites, growth factors, chloride ion, the calcium messenger system, and others capable of regulating/modulating steroid hormone biosynthesis, and in many cases steroidogenic acute regulatory protein expression, are discussed in this review.
498 citations
TL;DR: This review focuses on recent studies highlighting the importance of the oocyte in producing cAMP to maintain arrest, and discusses possible targets at the level of the Oocyte on which LH could act to stimulate meiotic resumption.
Abstract: Mammalian oocytes grow and undergo meiosis within ovarian follicles. Oocytes are arrested at the first meiotic prophase, held in meiotic arrest by the surrounding follicle cells until a surge of LH from the pituitary stimulates the immature oocyte to resume meiosis. Meiotic arrest depends on a high level of cAMP within the oocyte. This cAMP is generated by the oocyte, through the stimulation of the G(s) G-protein by the G-protein-coupled receptor, GPR3. Stimulation of meiotic maturation by LH occurs via its action on the surrounding somatic cells rather than on the oocyte itself. LH induces the expression of epidermal growth factor-like proteins in the mural granulosa cells that act on the cumulus cells to trigger oocyte maturation. The signaling pathway between the cumulus cells and the oocyte, however, remains unknown. This review focuses on recent studies highlighting the importance of the oocyte in producing cAMP to maintain arrest, and discusses possible targets at the level of the oocyte on which LH could act to stimulate meiotic resumption.
457 citations
Cites background from "EGF-like growth factors as mediator..."
...Mural granulosa cells express RNA encoding epidermal growth factor (EGF)-like proteins within 1–3 h after LH receptor stimulation (Park et al. 2004, Ashkenazi et al. 2005), and these proteins, in particular amphiregulin and epiregulin, cause follicle-enclosed as well as cumulusenclosed oocytes to…...
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...Pharmacological inhibition of the EGF receptor in cultured follicles completely inhibits LHinduced oocyte maturation, further supporting a link between these EGF-like proteins and LH (Park et al. 2004)....
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References
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TL;DR: When epidermal growth factor and its relatives bind the ErbB family of receptors, they trigger a rich network of signalling pathways, culminating in responses ranging from cell division to death, motility to adhesion.
Abstract: When epidermal growth factor and its relatives bind the ErbB family of receptors, they trigger a rich network of signalling pathways, culminating in responses ranging from cell division to death, motility to adhesion. The network is often dysregulated in cancer and lends credence to the mantra that molecular understanding yields clinical benefit: over 25,000 women with breast cancer have now been treated with trastuzumab (Herceptin), a recombinant antibody designed to block the receptor ErbB2. Likewise, small-molecule enzyme inhibitors and monoclonal antibodies to ErbB1 are in advanced phases of clinical testing. What can this pathway teach us about translating basic science into clinical use?
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TL;DR: In this article, agents and methods for growth factor receptor activation by modulating the G-protein mediated signal transduction pathway were described, and a method to activate the growth factor receptors was proposed.
Abstract: The present invention relates to agents and methods for growth-factor receptor activation by modulating the G-protein mediated signal transduction pathway.
1,608 citations
TL;DR: The receptor for epidermal growth factor was identified as a downstream element in different signaling pathways, expanding its classical function as a receptor for EGF-like ligands to a role as mediator of diverse signaling systems and as a switch point of a cellular communication network.
618 citations
TL;DR: The results provide genetic confirmation of a requirement for EGFR signaling throughout the development of the mouse mammary gland, and reveal stage-dependent activities for different EGFR ligands.
Abstract: Targeted mice lacking functional EGF or amphiregulin (AR) were derived and bred to the TGFalpha-knockout to generate mice lacking various combinations of the three ligands. In contrast to EGF receptor (EGFR) knockout mice, triple null mice lacking half of the EGFR ligand family were healthy and fertile, indicative of overlapping or compensatory functions among EGF family members. Nevertheless, pups born to triple null dams frequently died or were runted, suggesting a mammary gland defect. Comparison of individual and combinatorial knockouts established that specific loss of AR severely stunted ductal outgrowth during puberty, consistent with dramatic expression of AR transcripts in normal developing ducts. Surprisingly, loss of all three ligands did not significantly affect cellular proliferation, apoptosis, or ERK activation within terminal end buds. Following pregnancy, most AR single null females, but few triple null females could nurse their young, revealing collaborative roles for EGF and TGFalpha in mammopoiesis and lactogenesis. In triple null glands, alveoli were poorly organized and differentiated, and milk protein gene expression was decreased. Additionally, Stat5a activation was frequently reduced in AR single and combinatorial nulls in association with impaired lactation. Collectively, our results provide genetic confirmation of a requirement for EGFR signaling throughout the development of the mouse mammary gland, and reveal stage-dependent activities for different EGFR ligands. Finally, the additional loss of growth factors from pups nursed by triple null dams further worsened their survival and growth, establishing functions for both maternal- and neonatal-derived growth factors.
558 citations
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