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Life Science Alliance Oct 2023Estradiol and progesterone are the primary sex steroids produced by the ovary. Upon luteinizing hormone surge, estradiol-producing granulosa cells convert into...
Estradiol and progesterone are the primary sex steroids produced by the ovary. Upon luteinizing hormone surge, estradiol-producing granulosa cells convert into progesterone-producing cells and eventually become large luteal cells of the corpus luteum. Signaling pathways and transcription factors involved in the cessation of estradiol and simultaneous stimulation of progesterone production in granulosa cells are not clearly understood. Here, we decipher that phosphorylated ERK1/2 regulates granulosa cell steroidogenesis by inhibiting estradiol and inducing progesterone production. Down-regulation of transcription factor FOXL2 and up-regulation of SOX9 by ERK underpin its differential steroidogenic function. Interestingly, the incidence of SOX9 is largely uncovered in ovarian cells and is found to regulate FOXL2 along with CYP19A1 and STAR genes, encoding rate-limiting enzymes of steroidogenesis, in cultured granulosa cells. We propose that the novel ERK1/2-SOX9/FOXL2 axis in granulosa cells is a critical regulator of ovarian steroidogenesis and may be considered when addressing pathophysiologies associated with inappropriate steroid production and infertility in humans and animals.
Topics: Female; Humans; Animals; Ovary; Progesterone; MAP Kinase Signaling System; Corpus Luteum; Estradiol; Forkhead Box Protein L2; SOX9 Transcription Factor
PubMed: 37532283
DOI: 10.26508/lsa.202302100 -
Frontiers in Endocrinology 2023Macrophages (MΦs) are the most abundant leukocytes in mammalian ovaries that have heterogeneity and plasticity. A body of evidence has indicated that these cells are... (Review)
Review
Macrophages (MΦs) are the most abundant leukocytes in mammalian ovaries that have heterogeneity and plasticity. A body of evidence has indicated that these cells are important in maintaining ovarian homeostasis and they play critical roles in ovarian physiological events, such as folliculogenesis, ovulation, corpus luteum formation and regression. As females age, ovarian tissue microenvironment is typified by chronic inflammation with exacerbated ovarian fibrosis. In response to specific danger signals within aged ovaries, macrophages polarize into different M1 or M2 phenotypes, and specialize in unique functions to participate in the ovarian aging process. In this review, we will focus on the physiologic roles of MΦs in normal ovarian functions. Furthermore, we will discuss the roles of MΦs in the process of ovarian senescence, as well as the novel techniques applied in this field.
Topics: Female; Animals; Ovary; Ovulation; Macrophages; Leukocytes; Mammals
PubMed: 38027176
DOI: 10.3389/fendo.2023.1282658 -
BMC Genomics Jul 2023The development of asymmetric chick gonads involves separate developmental programs in the left and right gonads. In contrast to the left ovary developing into a fully...
BACKGROUND
The development of asymmetric chick gonads involves separate developmental programs in the left and right gonads. In contrast to the left ovary developing into a fully functional reproductive organ, the right ovary undergoes gradual degeneration. However, the molecular mechanisms underlying the the degeneration of the right ovary remain incompletely understood. In the present study, we investigated the histomorphological and transcriptomic changes in the right ovary of ducks and geese during the the embryonic stage up to post-hatching day 1.
RESULT
Hematoxylin-eosin stainings revealed that the right ovary developed until embryonic day 20 in ducks (DE20) or embryonic day 22 in geese (GE22), after which it started to regress. Further RNA-seq analyses revealed that both the differentially expressed genes (DEGs) in ducks and geese right ovary developmental stage were significantly enriched in cell adhesion-related pathway (ECM-receptor interaction, Focal adhesion pathway) and Cellular senescence pathway. Then during the degeneration stage, the DEGs were primarily enriched in pathways associated with inflammation, including Herpes simplex virus 1 infection, Influenza A, and Toll-like receptor signaling pathway. Moreover, duck-specific DEGs showed enrichment in Steroid hormone biosynthesis, Base excision repair, and the Wnt signaling pathway, while geese-specifically DEGs were found to be enriched in apoptosis and inflammation-related pathways, such as Ferroptosis, Necroptosis, RIG-I-like receptor signaling pathway, and NOD-like receptor signaling pathway. These findings suggest that the degeneration process of the right ovary in ducks occurs at a slower pace compared to that in geese. Additionally, the observation of the left ovary of the geese varying degeneration rates in the right ovary after hatching indicated that the development of the left ovary may be influenced by the degeneration of the right ovary.
CONCLUSION
The data presented in this study provide valuable insights into the dynamic changes in histological structure and transcriptome during the degeneration of the right ovary in ducks and geese. In addition, through the analysis of shared characteristics in the degeneration process of the right ovary in both ducks and geese, we have uncovered the patterns of degradation and elucidated the molecular mechanisms involved in the regression of the right ovary in poultry. Furthermore, we have also made initial discoveries regarding the relationship between the degeneration of the right ovary and the development of the left ovary.
Topics: Female; Animals; Ovary; Ducks; Geese; Transcriptome; Inflammation
PubMed: 37430218
DOI: 10.1186/s12864-023-09493-0 -
Developmental Cell Oct 2023Formation of either an ovary or a testis during human embryonic life is one of the most important sex-specific events leading to the emergence of secondary sexual...
Formation of either an ovary or a testis during human embryonic life is one of the most important sex-specific events leading to the emergence of secondary sexual characteristics and sex assignment of babies at birth. Our study focused on the sex-specific and sex-indifferent characteristics of the prenatal ovarian stromal cells, cortical cords, and germline, with the discovery that the ovarian mesenchymal cells of the stroma are transcriptionally indistinguishable from the mesenchymal cells of the testicular interstitium. We found that first-wave pre-granulosa cells emerge at week 7 from early supporting gonadal cells with stromal identity and are spatially defined by KRT19 levels. We also identified rare transient state f0 spermatogonia cells within the ovarian cords between weeks 10 and 16. Taken together, our work illustrates a unique plasticity of the embryonic ovary during human development.
Topics: Male; Female; Infant, Newborn; Humans; Ovary; Gonads; Testis; Germ Cells; Single-Cell Analysis
PubMed: 37582368
DOI: 10.1016/j.devcel.2023.07.014 -
Aging Oct 2023The ovarian microenvironment becomes fibrotic and stiff with age, in part due to increased collagen and decreased hyaluronan. However, the extracellular matrix (ECM) is...
The ovarian microenvironment becomes fibrotic and stiff with age, in part due to increased collagen and decreased hyaluronan. However, the extracellular matrix (ECM) is a complex network of hundreds of proteins, glycoproteins, and glycans which are highly tissue specific and undergo pronounced changes with age. To obtain an unbiased and comprehensive profile of age-associated alterations to the murine ovarian proteome and ECM, we used a label-free quantitative proteomic methodology. We validated conditions to enrich for the ECM prior to proteomic analysis. Following analysis by data-independent acquisition (DIA) and quantitative data processing, we observed that both native and ECM-enriched ovaries clustered separately based on age, indicating distinct age-dependent proteomic signatures. We identified a total of 4,721 proteins from both native and ECM-enriched ovaries, of which 383 proteins were significantly altered with advanced age, including 58 ECM proteins. Several ECM proteins upregulated with age have been associated with fibrosis in other organs, but to date their roles in ovarian fibrosis are unknown. Pathways regulating DNA metabolism and translation were downregulated with age, whereas pathways involved in ECM remodeling and immune response were upregulated. Interestingly, immune-related pathways were upregulated with age even in ECM-enriched ovaries, suggesting a novel interplay between the ECM and the immune system. Moreover, we identified putative markers of unique immune cell populations present in the ovary with age. These findings provide evidence from a proteomic perspective that the aging ovary provides a fibroinflammatory milieu, and our study suggests target proteins which may drive these age-associated phenotypes for future investigation.
Topics: Female; Animals; Mice; Ovary; Proteomics; Extracellular Matrix; Extracellular Matrix Proteins; Fibrosis
PubMed: 37899138
DOI: 10.18632/aging.205190 -
Life Science Alliance Nov 2023Gametogenesis is a complex and sex-specific multistep process during which the gonadal somatic niche plays an essential regulatory role. One of the most crucial steps...
Gametogenesis is a complex and sex-specific multistep process during which the gonadal somatic niche plays an essential regulatory role. One of the most crucial steps during human female gametogenesis is the formation of primordial follicles, the functional unit of the ovary that constitutes the pool of follicles available at birth during the entire reproductive life. However, the relation between human fetal germ cells (hFGCs) and gonadal somatic cells during the formation of the primordial follicles remains largely unexplored. We have discovered that hFGCs can form multinucleated syncytia, some connected via interconnecting intercellular bridges, and that not all nuclei in hFGC-syncytia were synchronous regarding meiotic stage. As hFGCs progressed in development, pre-granulosa cells formed protrusions that seemed to progressively constrict individual hFGCs, perhaps contributing to separate them from the multinucleated syncytia. Our findings highlighted the cell-cell interaction and molecular dynamics between hFGCs and (pre)granulosa cells during the formation of primordial follicles in humans. Knowledge on how the pool of primordial follicle is formed is important to understand human infertility.
Topics: Infant, Newborn; Male; Humans; Female; Ovary; Cell Communication; Cell Nucleus; Gametogenesis; Germ Cells
PubMed: 37643865
DOI: 10.26508/lsa.202301926 -
Nature Communications Sep 2023Most Drosophila transposable elements are LTR retrotransposons, some of which belong to the genus Errantivirus and share structural and functional characteristics with...
Most Drosophila transposable elements are LTR retrotransposons, some of which belong to the genus Errantivirus and share structural and functional characteristics with vertebrate endogenous retroviruses. Like endogenous retroviruses, it is unclear whether errantiviruses retain some infectivity and transposition capacity. We created conditions where control of the Drosophila ZAM errantivirus through the piRNA pathway was abolished leading to its de novo reactivation in somatic gonadal cells. After reactivation, ZAM invaded the oocytes and severe fertility defects were observed. While ZAM expression persists in the somatic gonadal cells, the germline then set up its own adaptive genomic immune response by producing piRNAs against the constantly invading errantivirus, restricting invasion. Our results suggest that although errantiviruses are continuously repressed by the piRNA pathway, they may retain their ability to infect the germline and transpose, thus allowing them to efficiently invade the germline if they are expressed.
Topics: Animals; Female; Drosophila; Ovary; Drosophila melanogaster; Germ Cells; Drosophila Proteins; Endogenous Retroviruses; RNA, Small Interfering; DNA Transposable Elements
PubMed: 37773253
DOI: 10.1038/s41467-023-41733-5 -
Frontiers in Endocrinology 2023Turner syndrome (TS) is a chromosomal disorder that affects about 1 in 2500 female births and is characterized by the partial or complete absence of the second X... (Review)
Review
Turner syndrome (TS) is a chromosomal disorder that affects about 1 in 2500 female births and is characterized by the partial or complete absence of the second X chromosome. Depending on karyotype, TS is associated with primary ovarian insufficiency (POI). Approximately 50% of girls with a mosaic 45, X/46, XX karyotype may enter puberty spontaneously, but only 5-10% of women with TS achieve pregnancy without egg donation. In this review, we will evaluate the clinical use of markers of ovarian function in TS patients. Based on longitudinal studies of serum concentrations of reproductive hormones as well as ovarian morphology in healthy females and patients with TS, we will evaluate how they can be applied in a clinical setting. This is important when counseling patients and their families about future ovarian function essential for pubertal development and fertility. Furthermore, we will report on 20 years of experience of transition from pediatric to gynecological and adult endocrinological care in our center at Rigshospitalet, Copenhagen, Denmark.
Topics: Adult; Pregnancy; Child; Female; Humans; Turner Syndrome; Follow-Up Studies; Ovary; Longitudinal Studies; Puberty
PubMed: 37455919
DOI: 10.3389/fendo.2023.1173600 -
Frontiers in Endocrinology 2023The number of primordial follicles (PFs) in mammals determines the ovarian reserve, and impairment of primordial follicle formation (PFF) will cause premature ovarian...
INTRODUCTION
The number of primordial follicles (PFs) in mammals determines the ovarian reserve, and impairment of primordial follicle formation (PFF) will cause premature ovarian insufficiency (POI).
METHODS
By analyzing public single-cell RNA sequencing performed during PFF on mice and human ovaries, we identified novel functional genes and novel ligand-receptor interaction during PFF. Based on immunofluorescence and in vitro ovarian culture, we confirmed mechanisms of genes and ligand-receptor interaction in PFF. We also applied whole exome sequencing (WES) in 93 cases with POI and whole genome sequencing (WGS) in 465 controls. Variants in POI patients were further investigated by in silico analysis and functional verification.
RESULTS
We revealed ANXA7 (annexin A7) and GTF2F1 (general transcription factor IIF subunit 1) in germ cells to be novel potentially genes in promoting PFF. Ligand Mdk (midkine) in germ cells and its receptor Sdc1 (syndecan 1) in granulosa cells are novel interaction crucial for PFF. Based on immunofluorescence, we confirmed significant up-regulation of ANXA7 in PFs compared with germline cysts, and uniform expression of GTF2F1, MDK and SDC1 during PFF, in 25 weeks human fetal ovary. In vitro investigation indicated that Anxa7 and Gtf2f1 are vital for mice PFF by regulating Jak/Stat3 and Jnk signaling pathways, respectively. Ligand-receptor (Mdk-Sdc1) are crucial for PFF by regulating Pi3k-akt signaling pathway. Two heterozygous variants in GTF2F1, and one heterozygous variants in SDC1 were identified in cases, but no variant were identified in controls. The protein level of GTF2F1 or SDC1 in POI cases are significantly lower than that of controls, indicating the pathogenic effects of the two genes on ovarian function were dosage dependent.
DISCUSSION
Our study identified novel genes and novel ligand-receptor interaction during PFF, and further expanding the genetic architecture of POI.
Topics: Female; Humans; Animals; Mice; Exome Sequencing; Phosphatidylinositol 3-Kinases; Ligands; Single-Cell Gene Expression Analysis; Ovarian Follicle; Primary Ovarian Insufficiency; Menopause, Premature; Mammals
PubMed: 38149096
DOI: 10.3389/fendo.2023.1285667 -
Science Advances Oct 2023Cancer treatments can damage the ovarian follicle reserve, leading to primary ovarian insufficiency and infertility among survivors. Checkpoint kinase 2 (CHEK2)...
Cancer treatments can damage the ovarian follicle reserve, leading to primary ovarian insufficiency and infertility among survivors. Checkpoint kinase 2 (CHEK2) deficiency prevents elimination of oocytes in primordial follicles in female mice exposed to radiation and preserves their ovarian function and fertility. Here, we demonstrate that CHEK2 also coordinates the elimination of oocytes after exposure to standard-of-care chemotherapy drugs. CHEK2 activates two downstream targets-TAp63 and p53-which direct oocyte elimination. CHEK2 knockout or pharmacological inhibition preserved ovarian follicle reserve after radiation and chemotherapy. However, the lack of specificity for CHEK2 among available inhibitors limits their potential for clinical development. These findings demonstrate that CHEK2 is a master regulator of the ovarian cellular response to damage caused by radiation and chemotherapy and warrant the development of selective inhibitors specific to CHEK2 as a potential avenue for ovario-protective treatments.
Topics: Female; Animals; Mice; Checkpoint Kinase 2; Oocytes; Ovarian Follicle; Antineoplastic Agents; Ovary
PubMed: 37862420
DOI: 10.1126/sciadv.adg0898