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Reproductive Biology and Endocrinology... Jan 2019A central dogma of mammalian reproductive biology is that the size of the primordial follicle pool represents reproductive capacity in females. The assembly of the... (Review)
Review
A central dogma of mammalian reproductive biology is that the size of the primordial follicle pool represents reproductive capacity in females. The assembly of the primordial follicle starts after the primordial germ cells (PGCs)-derived oocyte releases from the synchronously dividing germline cysts. PGCs initiate meiosis during fetal development. However, after synapsis and recombination of homologous chromosomes, they arrest at the diplotene stage of the first meiotic prophase (MI). The diplotene-arrested oocyte, together with the surrounding of a single layer of flattened granulosa cells, forms a basic unit of the ovary, the primordial follicle. At the start of each estrous (animal) or menstrual cycle (human), in response to a surge of luteinizing hormone (LH) from the pituitary gland, a limited number of primordial follicles are triggered to develop into primary follicles, preantral follicles, antral follicles and reach to preovulatory follicle stage. During the transition from the preantral to antral stages, the enclosed oocyte gradually acquires the capacity to resume meiosis. Meiotic resumption from the prophase of MI is morphologically characterized by the dissolution of the oocyte nuclear envelope, which is generally termed the "germinal vesicle breakdown" (GVBD). Following GVBD and completion of MI, the oocyte enters meiosis II without an obvious S-phase and arrests at metaphase phase II (MII) until fertilization. The underlying mechanism of meiotic arrest has been widely explored in numerous studies. Many studies indicated that two cellular second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) play an essential role in maintaining oocyte meiotic arrest. This review will discuss how these two cyclic nucleotides regulate oocyte maturation by blocking or initiating meiotic processes, and to provide an insight in future research.
Topics: Animals; Cyclic AMP; Cyclic GMP; Female; Granulosa Cells; Humans; Mammals; Meiosis; Meiotic Prophase I; Metaphase; Models, Biological; Oocytes
PubMed: 30611263
DOI: 10.1186/s12958-018-0445-8 -
Proceedings of the National Academy of... Jun 2018MTOR (mechanistic target of rapamycin) is a widely recognized integrator of signals and pathways key for cellular metabolism, proliferation, and differentiation. Here we...
MTOR (mechanistic target of rapamycin) is a widely recognized integrator of signals and pathways key for cellular metabolism, proliferation, and differentiation. Here we show that conditional knockout (cKO) of in either primordial or growing oocytes caused infertility but differentially affected oocyte quality, granulosa cell fate, and follicular development. cKO of in nongrowing primordial oocytes caused defective follicular development leading to progressive degeneration of oocytes and loss of granulosa cell identity coincident with the acquisition of immature Sertoli cell-like characteristics. Although was deleted at the primordial oocyte stage, DNA damage accumulated in oocytes during their later growth, and there was a marked alteration of the transcriptome in the few oocytes that achieved the fully grown stage. Although oocyte quality and fertility were also compromised when was deleted after oocytes had begun to grow, these occurred without overtly affecting folliculogenesis or the oocyte transcriptome. Nevertheless, there was a significant change in a cohort of proteins in mature oocytes. In particular, down-regulation of PRC1 (protein regulator of cytokinesis 1) impaired completion of the first meiotic division. Therefore, MTOR-dependent pathways in primordial or growing oocytes differentially affected downstream processes including follicular development, sex-specific identity of early granulosa cells, maintenance of oocyte genome integrity, oocyte gene expression, meiosis, and preimplantation developmental competence.
Topics: Animals; Cell Differentiation; Cells, Cultured; Female; Follicle Stimulating Hormone; Granulosa Cells; Infertility, Female; Meiosis; Mice; Mice, Inbred C57BL; Mice, Knockout; Oocytes; Oogenesis; Ovarian Follicle; TOR Serine-Threonine Kinases
PubMed: 29784807
DOI: 10.1073/pnas.1800352115 -
Human Reproduction Update Jul 2023Regulated cell death is a fundamental component of numerous physiological processes; spanning from organogenesis in utero, to normal cell turnover during adulthood, as... (Review)
Review
BACKGROUND
Regulated cell death is a fundamental component of numerous physiological processes; spanning from organogenesis in utero, to normal cell turnover during adulthood, as well as the elimination of infected or damaged cells throughout life. Quality control through regulation of cell death pathways is particularly important in the germline, which is responsible for the generation of offspring. Women are born with their entire supply of germ cells, housed in functional units known as follicles. Follicles contain an oocyte, as well as specialized somatic granulosa cells essential for oocyte survival. Follicle loss-via regulated cell death-occurs throughout follicle development and life, and can be accelerated following exposure to various environmental and lifestyle factors. It is thought that the elimination of damaged follicles is necessary to ensure that only the best quality oocytes are available for reproduction.
OBJECTIVE AND RATIONALE
Understanding the precise factors involved in triggering and executing follicle death is crucial to uncovering how follicle endowment is initially determined, as well as how follicle number is maintained throughout puberty, reproductive life, and ovarian ageing in women. Apoptosis is established as essential for ovarian homeostasis at all stages of development and life. However, involvement of other cell death pathways in the ovary is less established. This review aims to summarize the most recent literature on cell death regulators in the ovary, with a particular focus on non-apoptotic pathways and their functions throughout the discrete stages of ovarian development and reproductive life.
SEARCH METHODS
Comprehensive literature searches were carried out using PubMed and Google Scholar for human, animal, and cellular studies published until August 2022 using the following search terms: oogenesis, follicle formation, follicle atresia, oocyte loss, oocyte apoptosis, regulated cell death in the ovary, non-apoptotic cell death in the ovary, premature ovarian insufficiency, primordial follicles, oocyte quality control, granulosa cell death, autophagy in the ovary, autophagy in oocytes, necroptosis in the ovary, necroptosis in oocytes, pyroptosis in the ovary, pyroptosis in oocytes, parthanatos in the ovary, and parthanatos in oocytes.
OUTCOMES
Numerous regulated cell death pathways operate in mammalian cells, including apoptosis, autophagic cell death, necroptosis, and pyroptosis. However, our understanding of the distinct cell death mediators in each ovarian cell type and follicle class across the different stages of life remains the source of ongoing investigation. Here, we highlight recent evidence for the contribution of non-apoptotic pathways to ovarian development and function. In particular, we discuss the involvement of autophagy during follicle formation and the role of autophagic cell death, necroptosis, pyroptosis, and parthanatos during follicle atresia, particularly in response to physiological stressors (e.g. oxidative stress).
WIDER IMPLICATIONS
Improved knowledge of the roles of each regulated cell death pathway in the ovary is vital for understanding ovarian development, as well as maintenance of ovarian function throughout the lifespan. This information is pertinent not only to our understanding of endocrine health, reproductive health, and fertility in women but also to enable identification of novel fertility preservation targets.
Topics: Adult; Animals; Female; Humans; Apoptosis; Granulosa Cells; Mammals; Oocytes; Ovarian Follicle; Ovary; Regulated Cell Death; Homeostasis
PubMed: 36857094
DOI: 10.1093/humupd/dmad005 -
Ecotoxicology and Environmental Safety Apr 2021Microplastics (MPs) considered as a new persistent environmental pollutant could enter into the circulatory system and result in decrease of sperm quantity and quality...
Microplastics (MPs) considered as a new persistent environmental pollutant could enter into the circulatory system and result in decrease of sperm quantity and quality in mice. However, the effects of Polystyrene MPs (PS MPs) on the ovary and its mechanism in rats remained unclear. In this present study, thirty-two healthy female Wistar rats were exposed to different concentrations of 0.5 µm PS MPs dispersed in deionized water for 90 days. Using hematoxylin-eosin (HE) staining, the number of growing follicles was decreased compared to the control group. In addition, the activity of glutathione peroxidase (GSH-Px), catalase (CAT) and superoxide dismutase (SOD) were decreased while the expression level of malondialdehyde (MDA) was increased in ovary tissue. Confirmed by immunohistochemistry, the integrated optical density of NLRP3 and Cleaved-Caspase-1 had been elevated by 13.9 and 14 in granulosa cells in the 1.5 mg/kg/d group. Furthermore, compared to the control group, the level of AMH had been decreased by 23.3 pg/ml while IL-1β and IL-18 had been increased by 32 and 18.5 pg/ml in the 1.5 mg/kg/d group using the enzyme-linked immune sorbent assay (ELISA). Besides, the apoptosis of granulosa cells was elevated measured by terminal deoxyribonucleotide transferase-mediated nick end labeling (TUNEL) staining and flow cytometry. Moreover, western blot assays showed that the expressions of NLRP3/Caspase-1 signaling pathway related factors and Cleaved-Caspase-3 were increased. These results demonstrated that PS MPs could induce pyroptosis and apoptosis of ovarian granulosa cells via the NLRP3/Caspase-1 signaling pathway maybe triggered by oxidative stress. The present study suggested that exposure to microplastics had adverse effects on ovary and could be a potential risk factor for female infertility, which provided new insights into the toxicity of MPs on female reproduction.
Topics: Animals; Apoptosis; Caspase 1; Female; Granulosa Cells; Interleukin-18; Interleukin-1beta; Malondialdehyde; Microplastics; NLR Family, Pyrin Domain-Containing 3 Protein; Ovary; Oxidative Stress; Polystyrenes; Pyroptosis; Rats; Rats, Wistar; Signal Transduction
PubMed: 33550074
DOI: 10.1016/j.ecoenv.2021.112012 -
Fertility and Sterility May 2022
Topics: Cells, Cultured; Estradiol; Female; Granulosa Cells; Humans; Progesterone
PubMed: 35512969
DOI: 10.1016/j.fertnstert.2022.03.007 -
Molecular and Cellular Endocrinology Jul 2021A naturally occurring bovine model with excess follicular fluid androstenedione (High A4), reduced fertility, and polycystic ovary syndrome (PCOS)-like characteristics...
A naturally occurring bovine model with excess follicular fluid androstenedione (High A4), reduced fertility, and polycystic ovary syndrome (PCOS)-like characteristics has been identified. We hypothesized High A4 granulosa cells (GCs) would exhibit altered cell proliferation and/or steroidogenesis. Microarrays of Control and High A4 GCs combined with Ingenuity Pathway Analysis indicated that High A4 GCs had cell cycle inhibition and increased expression of microRNAs that inhibit cell cycle genes. Granulosa cell culture confirmed that A4 treatment decreased GC proliferation, increased anti-Müllerian hormone, and increased mRNA for CTNNBIP1. Increased CTNNBIP1 prevents CTNNB1 from interacting with members of the WNT signaling pathway thereby inhibiting the cell cycle. Expression of CYP17A1 was upregulated in High A4 GCs presumably due to reduced FOS mRNA expression compared to Control granulosa cells. Furthermore, comparisons of High A4 GC with thecal and luteal cell transcriptomes indicated an altered cellular identity and function contributing to a PCOS-like phenotype.
Topics: Androstenedione; Animals; Cattle; Cell Proliferation; Cells, Cultured; Cellular Microenvironment; Female; Gene Expression Profiling; Gene Expression Regulation; Gene Regulatory Networks; Granulosa Cells; MicroRNAs; Models, Biological; Oligonucleotide Array Sequence Analysis; Primary Cell Culture
PubMed: 33905753
DOI: 10.1016/j.mce.2021.111288 -
Poultry Science Apr 2015The reproductive strategy for avian species that produce a sequence (or clutch) of eggs is dependent upon the maintenance of a small cohort of viable, undifferentiated... (Review)
Review
The reproductive strategy for avian species that produce a sequence (or clutch) of eggs is dependent upon the maintenance of a small cohort of viable, undifferentiated (prehierarchal) follicles. It is from this cohort that a single follicle is selected on an approximate daily basis to initiate rapid growth and final differentiation before ovulation. This review describes a working model in which follicles within this prehierarchal cohort are maintained in an undifferentiated state by inhibitory cell signaling until the time of selection. Ultimately, follicle selection represents a process in which a single undifferentiated follicle per day is predicted to escape such inhibitory mechanisms to begin rapid growth and final maturation before ovulation. Several processes initiated within the granulosa cell layer at selection are dependent upon G protein-coupled receptors signaling via cyclic adenosine monophosphate (cAMP), and several critical processes are described herein. Finally, reference is made to several practical outcomes that can result from understanding the process of selection, including applications within the poultry industry. Proximal factors and processes that mediate follicle selection can either extend or decrease the length of the laying sequence, and thus directly influence overall egg production. In particular, any aberration that results in the selection of more than one follicle per day will result in decreased egg production. More generally, in wild birds these processes are modified by prevailing environmental conditions and by social interactions to influence clutch size. The elucidation of cellular processes that regulate follicle selection can assist in the development of assisted reproductive technologies for application in threatened and endangered avian species.
Topics: Animals; Birds; Cell Differentiation; Cyclic AMP; Female; Granulosa Cells; Models, Biological; Ovarian Follicle; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 25535403
DOI: 10.3382/ps/peu008 -
Fertility and Sterility Mar 2013Lack of an objective, accurate, and noninvasive embryo assessment strategy remains one of the major challenges encountered in in vitro fertilization. Cumulus and mural... (Review)
Review
Lack of an objective, accurate, and noninvasive embryo assessment strategy remains one of the major challenges encountered in in vitro fertilization. Cumulus and mural granulosa cells reflect the characteristics of the oocyte, providing a noninvasive means to assess oocyte quality. Specifically, transcriptomic profiling of follicular cells may help identify biomarkers of oocyte and embryo competence. Current transcriptomics technologies include quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) for analysis of individual genes and microarrays and high-throughput deep sequencing for whole genome expression profiling. Recently, using qRT-PCR and microarray technologies, a multitude of studies correlated changes in cumulus or granulosa cell gene expression with clinically relevant outcome parameters, including in vitro embryo development and pregnancy. While the initial findings are promising, a clinical benefit from the use of identified biomarker genes remains to be demonstrated in randomized controlled trials.
Topics: Biomarkers; Cumulus Cells; Embryonic Development; Female; Fertilization in Vitro; Gene Expression Profiling; Genetic Markers; Granulosa Cells; Humans; Oocytes; Pregnancy
PubMed: 23498999
DOI: 10.1016/j.fertnstert.2013.01.129 -
International Journal of Molecular... Nov 2023Granulosa cells are crucial for the establishment and maintenance of bidirectional communication among oocytes. Various intercellular material exchange modes, including... (Review)
Review
Granulosa cells are crucial for the establishment and maintenance of bidirectional communication among oocytes. Various intercellular material exchange modes, including paracrine and gap junction, are used between them to achieve the efficient delivery of granulosa cell structural components, energy substrates, and signaling molecules to oocytes. Glucose metabolism and lipid metabolism are two basic energy metabolism pathways in granulosa cells; these are involved in the normal development of oocytes. Pyruvate, produced by granulosa cell glycolysis, is an important energy substrate for oocyte development. Granulosa cells regulate changes in intrafollicular hormone levels through the processing of steroid hormones to control the development process of oocytes. This article reviews the material exchange between oocytes and granulosa cells and expounds the significance of granulosa cells in the development of oocytes through both glucose metabolism and lipid metabolism. In addition, we discuss the effects of glucose and lipid metabolism on oocytes under pathological conditions and explore its relationship to polycystic ovary syndrome (PCOS). A series of changes were found in the endogenous molecules and ncRNAs that are related to glucose and lipid metabolism in granulosa cells under PCOS conditions. These findings provide a new therapeutic target for patients with PCOS; additionally, there is potential for improving the fertility of patients with PCOS and the clinical outcomes of assisted reproduction.
Topics: Female; Humans; Polycystic Ovary Syndrome; Lipid Metabolism; Glucose; Oocytes; Granulosa Cells
PubMed: 38003436
DOI: 10.3390/ijms242216247 -
Cell Communication and Signaling : CCS May 2022The LH surge is a pivotal event that triggers multiple key ovarian processes including oocyte maturation, cumulus expansion, follicular wall rupture and luteinization of...
BACKGROUND
The LH surge is a pivotal event that triggers multiple key ovarian processes including oocyte maturation, cumulus expansion, follicular wall rupture and luteinization of mural granulosa and theca cells. Recently, LH-dependent activation of the Hippo signaling pathway has been shown to be required for the differentiation of granulosa cells into luteal cells. Still, the precise interactions between Hippo and LH signaling in murine granulosa cells remain to be elucidated.
METHODS
To detect the expression of effectors of the Hippo pathway, western blot, immunohistochemical and RT-qPCR analyses were performed on granulosa cells treated with LH in vitro or isolated from immature mice treated with eCG and hCG. Cultured granulosa cells were pretreated with pharmacologic inhibitors to identify the signaling pathways involved in Hippo regulation by LH. To study the roles of Yap1 and Taz in the regulation of the LH signaling cascade, RT-qPCR and microarray analyses were done on granulosa cells from Yap1;Taz mice treated with an adenovirus to drive cre expression. RT-qPCR was performed to evaluate YAP1 binding to the Areg promoter following chromatin immunoprecipitation of granulosa cells collected from mice prior to or 60 min following hCG treatment.
RESULTS
Granulosa cells showed a transient increase in LATS1, YAP1 and TAZ phosphorylation levels in response to the ovulatory signal. This Hippo activation by LH was mediated by protein kinase A. Furthermore, Yap1 and Taz are required for the induction of several LH target genes such as Areg, Pgr and Ptgs2, and for the activation of the ERK1/2 pathway. Consistent with these results, there was a substantial overlap between genes that are upregulated by LH and those that are downregulated following loss of Yap1/Taz, highlighting a major role for Hippo in mediating LH actions in the ovulation process. Finally, we showed that there is a marked recruitment of YAP1 to the Areg promoter of granulosa cells in response to hCG stimulation.
CONCLUSIONS
Overall, these results indicate that Hippo collaborates with the cAMP/PKA and ERK1/2 pathways to participate in the precise regulation of the LH cascade, and that Areg, as a direct transcriptional target of YAP1, is involved in mediating its actions in the ovary. Video Abstract.
Topics: Amphiregulin; Animals; Female; Granulosa Cells; Luteinizing Hormone; Mice; Phosphorylation; Signal Transduction
PubMed: 35619099
DOI: 10.1186/s12964-022-00843-1