bims-cebooc Biomed News
on Cell biology of oocytes
Issue of 2024‒07‒21
nineteen papers selected by
Gabriele Zaffagnini, Centre for Genomic Regulation
  1. Live chromosome identifying and tracking reveals size-based spatial pathway of meiotic errors in oocytes.
  2. Regulation of Oocyte mRNA Metabolism: A Key Determinant of Oocyte Developmental Competence.
  3. Predicting Infertility: How Genetic Variants in Oocyte Spindle Genes Affect Egg Quality.
  4. The CCT chaperonin and actin modulate the ER and RNA-binding protein condensation during oogenesis to maintain translational repression of maternal mRNA and oocyte quality.
  5. Mechanisms of DNA Damage Response in Mammalian Oocytes.
  6. Maternal inheritance of functional centrioles in two parthenogenetic nematodes.
  7. MIB2 functions in oocyte meiosis by modulating chromatin configuration.
  8. Maternal genetic variants in kinesin motor domains prematurely increase egg aneuploidy.
  9. Coenocystic oogenesis - modification of or deviation from the germ cell cyst paradigm?
  10. The DNA double-strand break repair proteins γH2AX, RAD51, BRCA1, RPA70, KU80, and XRCC4 exhibit follicle-specific expression differences in the postnatal mouse ovaries from early to older ages.
  11. Beyond simple tails: poly(A) tail-mediated RNA epigenetic regulation.
  12. Ras promotes germline stem cell division in Drosophila ovaries.
  13. Cytoplasmic stirring by active carpets.
  14. The role of ER exit sites in maintaining P-body organization and transmitting ER stress response during Drosophila melanogaster oogenesis.
  15. TDRD1 phase separation drives intermitochondrial cement assembly to promote piRNA biogenesis and fertility.
  16. Factors affecting age at menopause and their relationship with ovarian reserve: a comprehensive review.
  17. Protease Expression in the Human and Rat Cumulus Oocyte Complex (COC) During the Periovulatory Period: A Role in COC Migration.
  18. ADR-2 regulates fertility and oocyte fate in C. elegans.
  19. Mechanism of LncRNA Gm2044 in germ cell development.
  1. Science. 2024 Jul 19. 385(6706): eadn5529
    Live chromosome identifying and tracking reveals size-based spatial pathway of meiotic errors in oocytes.
    Osamu Takenouchi, Yogo Sakakibara, Tomoya S Kitajima.
      Meiotic errors of relatively small chromosomes in oocytes result in egg aneuploidies that cause miscarriages and congenital diseases. Unlike somatic cells, which preferentially mis-segregate larger chromosomes, aged oocytes preferentially mis-segregate smaller chromosomes through unclear processes. Here, we provide a comprehensive three-dimensional chromosome identifying-and-tracking dataset throughout meiosis I in live mouse oocytes. This analysis reveals a prometaphase pathway that actively moves smaller chromosomes to the inner region of the metaphase plate. In the inner region, chromosomes are pulled by stronger bipolar microtubule forces, which facilitates premature chromosome separation, a major cause of segregation errors in aged oocytes. This study reveals a spatial pathway that facilitates aneuploidy of small chromosomes preferentially in aged eggs and implicates the role of the M phase in creating a chromosome size-based spatial arrangement.
    DOI:  https://doi.org/10.1126/science.adn5529
  2. Adv Anat Embryol Cell Biol. 2024 ;238 23-46
    Regulation of Oocyte mRNA Metabolism: A Key Determinant of Oocyte Developmental Competence.
    Alison F Ermisch, Jennifer R Wood.
      The regulation of mRNA transcription and translation is uncoupled during oogenesis. The reason for this uncoupling is two-fold. Chromatin is only accessible to the transcriptional machinery during the growth phase as it condenses prior to resumption of meiosis to ensure faithful segregation of chromosomes during meiotic maturation. Thus, transcription rates are high during this time period in order to produce all of the transcripts needed for meiosis, fertilization, and embryo cleavage until the newly formed embryonic genome becomes transcriptionally active. To ensure appropriate timing of key developmental milestones including chromatin condensation, resumption of meiosis, segregation of chromosomes, and polar body extrusion, the translation of protein from transcripts synthesized during oocyte growth must be temporally regulated. This is achieved by the regulation of mRNA interaction with RNA binding proteins and shortening and lengthening of the poly(A) tail. This chapter details the essential factors that regulate the dynamic changes in mRNA synthesis, storage, translation, and degradation during oocyte growth and maturation.
    Keywords:  Chromatin condensation; Maternal RNA degradation; RNA binding proteins; RNA polyadenylation; Transcriptional activity; Transcriptional quiescence
    DOI:  https://doi.org/10.1007/978-3-031-55163-5_2
  3. Adv Anat Embryol Cell Biol. 2024 ;238 1-22
    Predicting Infertility: How Genetic Variants in Oocyte Spindle Genes Affect Egg Quality.
    Leelabati Biswas, Karen Schindler.
      Successful reproduction relies on the union of a single chromosomally normal egg and sperm. Chromosomally normal eggs develop from precursor cells, called oocytes, that have undergone accurate chromosome segregation. The process of chromosome segregation is governed by the oocyte spindle, a unique cytoskeletal machine that splits chromatin content of the meiotically dividing oocyte. The oocyte spindle develops and functions in an idiosyncratic process, which is vulnerable to genetic variation in spindle-associated proteins. Human genetic variants in several spindle-associated proteins are associated with poor clinical fertility outcomes, suggesting that heritable etiologies for oocyte dysfunction leading to infertility exist and that the spindle is a crux for female fertility. This chapter examines the mammalian oocyte spindle through the lens of human genetic variation, covering the genes TUBB8, TACC3, CEP120, AURKA, AURKC, AURKB, BUB1B, and CDC20. Specifically, it explores how patient-identified variants perturb spindle development and function, and it links these molecular changes in the oocyte to their cognate clinical consequences, such as oocyte maturation arrest, elevated egg aneuploidy, primary ovarian insufficiency, and recurrent pregnancy loss. This discussion demonstrates that small genetic errors in oocyte meiosis can result in remarkably far-ranging embryonic consequences, and thus reveals the importance of the oocyte's fine machinery in sustaining life.
    Keywords:  Biomarkers; Egg; Fertility; Genetic variants; Genomics; In vitro fertilization; Infertility; Meiosis; Miscarriage; Mutation; Oocyte; Precision medicine; Pregnancy; Reproduction; Reproductive endocrinology; Reproductive medicine; Spindle; Spontaneous abortion
    DOI:  https://doi.org/10.1007/978-3-031-55163-5_1
  4. bioRxiv. 2024 Jul 04. pii: 2024.07.01.601596. [Epub ahead of print]
    The CCT chaperonin and actin modulate the ER and RNA-binding protein condensation during oogenesis to maintain translational repression of maternal mRNA and oocyte quality.
    Mohamed T Elaswad, Mingze Gao, Victoria E Tice, Cora G Bright, Grace M Thomas, Chloe Munderloh, Nicholas J Trombley, Christya N Haddad, Ulysses G Johnson, Ashley N Cichon, Jennifer A Schisa.
      The regulation of maternal mRNAs is essential for proper oogenesis, the production of viable gametes, and to avoid birth defects and infertility. Many oogenic RNA-binding proteins have been identified with roles in mRNA metabolism, some of which localize to dynamic ribonucleoprotein granules and others that appear dispersed. Here, we use a combination of in vitro condensation assays and the in vivo C. elegans oogenesis model to determine the intrinsic properties of the conserved KH-domain MEX-3 protein and to identify novel regulators of MEX-3 and the Lsm protein, CAR-1. We demonstrate that MEX-3 undergoes liquid-liquid phase separation and appears to have intrinsic gel-like properties in vitro . We also identify novel roles for the CCT chaperonin and actin in preventing ectopic RNA-binding protein condensates in maturing oocytes that appear to be independent of MEX-3 folding. CCT and actin also oppose the expansion of ER sheets that may promote ectopic condensation of RNA-binding proteins that are associated with de-repression of maternal mRNA. This regulatory network is essential to preserve oocyte quality, prevent infertility, and may have implications for understanding the role of hMex3 phase transitions in cancer.Significance statement: The molecular mechanisms that regulate phase transitions of oogenic RNA-binding proteins are critical to elucidate but are not fully understood.We identify novel regulators of RNA-binding protein phase transitions in maturing oocytes that are required to maintain translational repression of maternal mRNAs and oocyte quality.This study is the first to elucidate a regulatory network involving the CCT chaperonin, actin, and the ER for phase transitions of RNA-binding proteins during oogenesis. Our findings for the conserved MEX-3 protein may also be applicable to better understanding the role of hMex3 phase transitions in cancer.
    DOI:  https://doi.org/10.1101/2024.07.01.601596
  5. Adv Anat Embryol Cell Biol. 2024 ;238 47-68
    Mechanisms of DNA Damage Response in Mammalian Oocytes.
    Fei Sun, Peter Sutovsky, Amanda L Patterson, Ahmed Z Balboula.
      DNA damage poses a significant challenge to all eukaryotic cells, leading to mutagenesis, genome instability and senescence. In somatic cells, the failure to repair damaged DNA can lead to cancer development, whereas, in oocytes, it can lead to ovarian dysfunction and infertility. The response of the cell to DNA damage entails a series of sequential and orchestrated events including sensing the DNA damage, activating DNA damage checkpoint, chromatin-related conformational changes, activating the DNA damage repair machinery and/or initiating the apoptotic cascade. This chapter focuses on how somatic cells and mammalian oocytes respond to DNA damage. Specifically, we will discuss how and why fully grown mammalian oocytes differ drastically from somatic cells and growing oocytes in their response to DNA damage.
    Keywords:  Aging; Autophagy; DNA damage repair; DNA damage response; Meiosis; Oocyte; PARP
    DOI:  https://doi.org/10.1007/978-3-031-55163-5_3
  6. Nat Commun. 2024 Jul 18. 15(1): 6042
    Maternal inheritance of functional centrioles in two parthenogenetic nematodes.
    Aurélien Perrier, Nadège Guiglielmoni, Delphine Naquin, Kevin Gorrichon, Claude Thermes, Sonia Lameiras, Alexander Dammermann, Philipp H Schiffer, Maia Brunstein, Julie C Canman, Julien Dumont.
      Centrioles are the core constituent of centrosomes, microtubule-organizing centers involved in directing mitotic spindle assembly and chromosome segregation in animal cells. In sexually reproducing species, centrioles degenerate during oogenesis and female meiosis is usually acentrosomal. Centrioles are retained during male meiosis and, in most species, are reintroduced with the sperm during fertilization, restoring centriole numbers in embryos. In contrast, the presence, origin, and function of centrioles in parthenogenetic species is unknown. We found that centrioles are maternally inherited in two species of asexual parthenogenetic nematodes and identified two different strategies for maternal inheritance evolved in the two species. In Rhabditophanes diutinus, centrioles organize the poles of the meiotic spindle and are inherited by both the polar body and embryo. In Disploscapter pachys, the two pairs of centrioles remain close together and are inherited by the embryo only. Our results suggest that maternally-inherited centrioles organize the embryonic spindle poles and act as a symmetry-breaking cue to induce embryo polarization. Thus, in these parthenogenetic nematodes, centrioles are maternally-inherited and functionally replace their sperm-inherited counterparts in sexually reproducing species.
    DOI:  https://doi.org/10.1038/s41467-024-50427-5
  7. Mol Cell Proteomics. 2024 Jul 15. pii: S1535-9476(24)00103-8. [Epub ahead of print] 100813
    MIB2 functions in oocyte meiosis by modulating chromatin configuration.
    Yifei Jin, Guangyi Sun, Jiashuo Li, Qing Cheng, Hongzheng Sun, Longsen Han, Xuejiang Guo, Shuai Zhu, Qiang Wang.
      Chromatin configuration serves as a principal indicator of GV (germinal vesicle)-stage oocyte quality. However, the underlying mechanisms governing the chromatin configuration transition from NSN (non-surrounded nucleolus) to SN (surrounded nucleolus) remain unclear. In this study, by conducting a quantitative proteomic analysis, we identified an increased expression of the MIB2 (MIB E3 ubiquitin protein ligase 2) protein in SN oocytes. Specific depletion of MIB2 in SN oocytes not only leads to severe disruption of the meiotic apparatus and a higher incidence of aneuploidy, but also adversely affects meiotic maturation and early embryo development. Notably, overexpression of MIB2 in NSN oocytes facilitates the chromatin configuration transition. Meantime, we observed that forced expression of MIB2 in NSN oocytes significantly mitigates spindle/chromosome disorganization and aneuploidy. In summary, our results suggest that chromatin configuration transition regulated by MIB2 is crucial for oocyte to acquire the developmental competence.
    Keywords:  Chromatin configuration; MIB2; meiosis; oocyte; proteomics
    DOI:  https://doi.org/10.1016/j.mcpro.2024.100813
  8. medRxiv. 2024 Jul 05. pii: 2024.07.04.24309950. [Epub ahead of print]
    Maternal genetic variants in kinesin motor domains prematurely increase egg aneuploidy.
    Leelabati Biswas, Katarzyna M Tyc, Mansour Aboelenain, Siqi Sun, Iva Dundović, Kruno Vukušić, Jason Liu, Vanessa Guo, Min Xu, Richard T Scott, Xin Tao, Iva M Tolić, Jinchuan Xing, Karen Schindler.
      The female reproductive lifespan depends on egg quality, particularly euploidy. Mistakes in meiosis leading to egg aneuploidy are common, but the genetic landscape causing this is not well understood due to limited phenotypic data. We identify genetic determinants of reproductive aging via egg aneuploidy using a biobank of maternal exomes linked with maternal age and embryonic aneuploidy data. We found 404 genes with variants enriched in individuals with high egg aneuploidy rates and implicate kinesin protein family genes in aneuploidy risk. Experimental perturbations showed that motor domain variants in these genes increase aneuploidy in mouse oocytes. A knock-in mouse model validated that a specific variant in kinesin KIF18A accelerates reproductive aging and diminishes fertility. These findings suggest potential non-invasive biomarkers for egg quality, aiding personalized fertility medicine.One sentence summary: The study identifies novel genetic determinants of reproductive aging linked to egg aneuploidy by analyzing maternal exomes and demonstrates that variants in kinesin genes, specifically KIF18A , contribute to increased aneuploidy and accelerated reproductive aging, offering potential for personalized fertility medicine.
    DOI:  https://doi.org/10.1101/2024.07.04.24309950
  9. Int J Dev Biol. 2024 Jul 09. 68(2): 47-53
    Coenocystic oogenesis - modification of or deviation from the germ cell cyst paradigm?
    Malgorzata Kloc.
      Invertebrate and vertebrate species have many unusual cellular structures, such as long- or short-lived cell-in-cell structures and coenocytes. Coenocytes (often incorrectly described as syncytia) are multinuclear cells derived, unlike syncytia, not from the fusion of multiple cells but from multiple nuclear divisions without cytokinesis. An example of a somatic coenocyte is the coenocytic blastoderm in Drosophila. An astonishing property of coenocytes is the ability to differentiate the nuclei sharing a common cytoplasm into different subpopulations with different fate trajectories. An example of a germline coenocyte is the oogenic precursor of appendicularian tunicates, which shares many features with the somatic coenocyte of Drosophila. The germline coenocyte (coenocyst) is quite an unexpected structure because in most animals, including Drosophila, Xenopus, and mice, oogenesis proceeds within a group (cyst, nest) of sibling cells (cystocytes) connected by the intercellular bridges (ring canals, RCs) derived from multiple divisions with incomplete cytokinesis of a progenitor cell called the cystoblast. Here, I discuss the differences and similarities between cystocyte-based and coenocyst-based oogenesis, and the resemblance of coenocystic oogenesis to coenocytic somatic blastoderm in Drosophila. I also describe cell-in-cell structures that although not mechanistically, cytologically, or molecularly connected to somatic or germline coenocytes, are both unorthodox and intriguing cytological phenomena rarely covered by scientific literature.
    DOI:  https://doi.org/10.1387/ijdb.240064mk
  10. J Assist Reprod Genet. 2024 Jul 18.
    The DNA double-strand break repair proteins γH2AX, RAD51, BRCA1, RPA70, KU80, and XRCC4 exhibit follicle-specific expression differences in the postnatal mouse ovaries from early to older ages.
    Gunel Talibova, Yesim Bilmez, Betul Tire, Saffet Ozturk.
      PURPOSE: Ovarian aging is closely related to a decrease in follicular reserve and oocyte quality. The precise molecular mechanisms underlying these reductions have yet to be fully elucidated. Herein, we examine spatiotemporal distribution of key proteins responsible for DNA double-strand break (DSB) repair in ovaries from early to older ages. Functional studies have shown that the γH2AX, RAD51, BRCA1, and RPA70 proteins play indispensable roles in HR-based repair pathway, while the KU80 and XRCC4 proteins are essential for successfully operating cNHEJ pathway.METHODS: Female Balb/C mice were divided into five groups as follows: Prepuberty (3 weeks old; n = 6), puberty (7 weeks old; n = 7), postpuberty (18 weeks old; n = 7), early aged (52 weeks old; n = 7), and late aged (60 weeks old; n = 7). The expression of DSB repair proteins, cellular senescence (β-GAL) and apoptosis (cCASP3) markers was evaluated in the ovaries using immunohistochemistry.
    RESULT: β-GAL and cCASP3 levels progressively increased from prepuberty to aged groups (P < 0.05). Notably, γH2AX levels varied in preantral and antral follicles among the groups (P < 0.05). In aged groups, RAD51, BRCA1, KU80, and XRCC4 levels increased (P < 0.05), while RPA70 levels decreased (P < 0.05) compared to the other groups.
    CONCLUSIONS: The observed alterations were primarily attributed to altered expression in oocytes and granulosa cells of the follicles and other ovarian cells. As a result, the findings indicate that these DSB repair proteins may play a role in the repair processes and even other related cellular events in ovarian cells from early to older ages.
    Keywords:  DNA double-strand break; Female infertility; Follicles; HR repair; Oocytes; Ovarian aging; cNHEJ
    DOI:  https://doi.org/10.1007/s10815-024-03189-4
  11. Trends Biochem Sci. 2024 Jul 13. pii: S0968-0004(24)00161-0. [Epub ahead of print]
    Beyond simple tails: poly(A) tail-mediated RNA epigenetic regulation.
    Jingwen Liu, Falong Lu.
      The poly(A) tail is an essential structural component of mRNA required for the latter's stability and translation. Recent technologies have enabled transcriptome-wide profiling of the length and composition of poly(A) tails, shedding light on their overlooked regulatory capacities. Notably, poly(A) tails contain not only adenine but also uracil, cytosine, and guanine residues. These findings strongly suggest that poly(A) tails could encode a wealth of regulatory information, similar to known reversible RNA chemical modifications. This review aims to succinctly summarize our current knowledge on the composition, dynamics, and regulatory functions of RNA poly(A) tails. Given their capacity to carry rich regulatory information beyond the genetic code, we propose the concept of 'poly(A) tail epigenetic information' as a new layer of RNA epigenetic regulation.
    Keywords:  RNA epigenetics; oocyte-to-embryo transition; poly(A) tail; poly(A) tail epigenetic information; polyadenylation; re-polyadenylation
    DOI:  https://doi.org/10.1016/j.tibs.2024.06.013
  12. Stem Cell Reports. 2024 Jul 03. pii: S2213-6711(24)00185-1. [Epub ahead of print]
    Ras promotes germline stem cell division in Drosophila ovaries.
    Qi Zhang, Yanfang Wang, Zhenan Bu, Yang Zhang, Qian Zhang, Le Li, Lizhong Yan, Yuejia Wang, Shaowei Zhao.
      The Ras family genes are proto-oncogenes that are highly conserved from Drosophila to humans. In Drosophila, RasV12 is a constitutively activated form of the Ras oncoprotein, and its function in cell-cycle progression is context dependent. However, how it influences the cell cycle of female germline stem cells (GSCs) still remains unknown. Using both wild-type GSCs and bam mutant GSC-like cells as model systems, here we determined that RasV12 overexpression promotes GSC division, not growth, opposite to that in somatic wing disc cells. Ras performs this function through activating the mitogen-activated protein kinase (MAPK) signaling. This signaling is activated specifically in the M phase of mitotic germ cells, including both wild-type GSCs and bam mutant GSC-like cells. Furthermore, RasV12 overexpression triggers polyploid nurse cells to die through inducing mitotic stress. Given the similarities between Drosophila and mammalian GSCs, we propose that the Ras/MAPK signaling also promotes mammalian GSC division.
    Keywords:  Drosophila; MAPK; Ras; bam; germline stem cell
    DOI:  https://doi.org/10.1016/j.stemcr.2024.06.005
  13. Proc Natl Acad Sci U S A. 2024 Jul 23. 121(30): e2405114121
    Cytoplasmic stirring by active carpets.
    Brato Chakrabarti, Manas Rachh, Stanislav Y Shvartsman, Michael J Shelley.
      Large cells often rely on cytoplasmic flows for intracellular transport, maintaining homeostasis, and positioning cellular components. Understanding the mechanisms of these flows is essential for gaining insights into cell function, developmental processes, and evolutionary adaptability. Here, we focus on a class of self-organized cytoplasmic stirring mechanisms that result from fluid-structure interactions between cytoskeletal elements at the cell cortex. Drawing inspiration from streaming flows in late-stage fruit fly oocytes, we propose an analytically tractable active carpet theory. This model deciphers the origins and three-dimensional spatiotemporal organization of such flows. Through a combination of simulations and weakly nonlinear theory, we establish the pathway of the streaming flow to its global attractor: a cell-spanning vortical twister. Our study reveals the inherent symmetries of this emergent flow, its low-dimensional structure, and illustrates how complex fluid-structure interaction aligns with classical solutions in Stokes flow. This framework can be easily adapted to elucidate a broad spectrum of self-organized, cortex-driven intracellular flows.
    Keywords:  active matter; biophysics; cytoplasmic streaming; development; hydrodynamics
    DOI:  https://doi.org/10.1073/pnas.2405114121
  14. bioRxiv. 2024 Jul 05. pii: 2024.07.03.601952. [Epub ahead of print]
    The role of ER exit sites in maintaining P-body organization and transmitting ER stress response during Drosophila melanogaster oogenesis.
    Samantha N Milano, Livia V Bayer, Julie J Ko, Caroline E Casella, Diana P Bratu.
      Processing bodies (P-bodies) are cytoplasmic membrane-less organelles which host multiple mRNA processing events. While the fundamental principles of P-body organization are beginning to be elucidated in vitro , a nuanced understanding of how their assembly is regulated in vivo remains elusive. Here, we investigate the potential link between ER exit sites and P-bodies in Drosophila melanogaster egg chambers. Employing a combination of live and super-resolution imaging, we found that P-bodies associated with ER exit sites are larger and less mobile than cytoplasmic P-bodies, indicating that they constitute a distinct class of P-bodies which are more mature than their cytoplasmic counterparts. Moreover, we demonstrate that altering the composition of ER exit sites has differential effects on core P-body proteins (Me31B, Cup, and Trailer Hitch) suggesting a potential role for ER exit sites in P-body organization. We further show that in the absence of ER exit sites, P-body integrity is compromised and the stability and translational repression efficiency of the maternal mRNA, oskar , are reduced. Finally, we show that ER stress is communicated to P-bodies via ER exit sites, highlighting the pivotal role of ER exit sites as a bridge between membrane-bound and membrane-less organelles in ER stress response. Together, our data unveils the significance of ER exit sites not only in governing P-body organization, but also in facilitating inter-organellar communication during stress, potentially bearing implications for a variety of disease pathologies.
    DOI:  https://doi.org/10.1101/2024.07.03.601952
  15. Dev Cell. 2024 Jul 16. pii: S1534-5807(24)00395-2. [Epub ahead of print]
    TDRD1 phase separation drives intermitochondrial cement assembly to promote piRNA biogenesis and fertility.
    Jie Gao, Jiongjie Jing, Guanyi Shang, Canmei Chen, Maoping Duan, Wenyang Yu, Ke Wang, Jie Luo, Manxiu Song, Kun Chen, Chen Chen, Tuo Zhang, Deqiang Ding.
      The intermitochondrial cement (IMC) is a prominent germ granule that locates among clustered mitochondria in mammalian germ cells. Serving as a key platform for Piwi-interacting RNA (piRNA) biogenesis; however, how the IMC assembles among mitochondria remains elusive. Here, we identify that Tudor domain-containing 1 (TDRD1) triggers IMC assembly via phase separation. TDRD1 phase separation is driven by the cooperation of its tetramerized coiled-coil domain and dimethylarginine-binding Tudor domains but is independent of its intrinsically disordered region. TDRD1 is recruited to mitochondria by MILI and sequentially enhances mitochondrial clustering and triggers IMC assembly via phase separation to promote piRNA processing. TDRD1 phase separation deficiency in mice disrupts IMC assembly and piRNA biogenesis, leading to transposon de-repression and spermatogenic arrest. Moreover, TDRD1 phase separation is conserved in vertebrates but not in invertebrates. Collectively, our findings demonstrate a role of phase separation in germ granule formation and establish a link between membrane-bound organelles and membrane-less organelles.
    Keywords:  IMC; MILI; TDRD1; Tudor; coiled coil; germ granule; oligomerization; phase separation; piRNA; spermatogenesis
    DOI:  https://doi.org/10.1016/j.devcel.2024.06.017
  16. Eur J Contracept Reprod Health Care. 2024 Jul 15. 1-11
    Factors affecting age at menopause and their relationship with ovarian reserve: a comprehensive review.
    Antonio La Marca, Marialaura Diamanti.
      OBJECTIVE: The aim of this article was to discuss all the factors affecting the age at menopause and their correlation with ovarian reserve.MATERIALS AND METHODS: A narrative review of original articles was performed using PubMed until December 2023. The following keywords were used to generate the list of citations: 'menopause', 'ovarian reserve' 'oocytes quality and quantity', 'ovarian ageing'.
    RESULTS: Menopause is the final step in the process of ovarian ageing and is influenced by the oocyte pool at birth. Conditions that accelerate follicle depletion during the reproductive lifespan lead to premature ovarian insufficiency (POI) and premature ovarian failure (POF), while a higher ovarian reserve is associated with a delayed time to menopause. Reproductive history, sociodemographic, lifestyle and iatrogenic factors may impact ovarian reserve and the age at menopause.
    CONCLUSIONS: Some factors affecting the age at menopause are modifiable and the risks of early menopause may be preventable. We hypothesise that by addressing these modifiable factors we may also preserve ovarian reserve. However, further interventional studies are needed to evaluate the effects of the described strategies on ovarian reserve.
    Keywords:  Menopause; oocytes quality; oocytes quantity; ovarian ageing; ovarian reserve
    DOI:  https://doi.org/10.1080/13625187.2024.2375281
  17. Biol Reprod. 2024 Jul 17. pii: ioae108. [Epub ahead of print]
    Protease Expression in the Human and Rat Cumulus Oocyte Complex (COC) During the Periovulatory Period: A Role in COC Migration.
    Ketan Shrestha, Muraly Puttabyatappa, Michelle A Wynn, Patrick R Hannon, Linah F Al-Alem, Katherine L Rosewell, James Akin, Thomas E Curry.
      The migratory and matrix-invading capacities of the cumulus oocyte complex (COC) have been shown to be important for the ovulatory process. In metastatic cancers, these capacities are due to increased expression of proteases, however, there is limited information on protease expression in the COCs. The present study examined COC expression of plasmins, matrix metalloproteases (MMP) and A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTS) family members in the rat and human. In the rat, hCG administration increased COC expression of Mmp2, Mmp9, Mmp13, Mmp14, Mmp16, Adamts1, and the protease inhibitors Timp1, Timp3 and Serpine1 by 8-12 hours. This ovulatory induction of proteases in vivo could be mimicked by forskolin and ampiregulin treatment of cultured rat COCs with increases observed in Mmp2, Mmp13, Mmp14, Mmp16, Mmp19, Plat, and the protease inhibitors Timp1, Timp3 and Serpine1. Comparison of expression between rat COCs and granulosa cells at the time of ovulation showed decreased Mmp9 and increased Mmp13, Mmp14, Mmp16, Adamts1, Timp1 and Timp3 expression in the COCs. In human, comparison of expression between cumulus and granulosa cells at the time of IVF retrieval showed decreased MMP1, MMP2, MMP9, and ADAMTS1, while expression of MMP16, TIMP1, and TIMP3 were increased. Treatment of expanding rat COCs with a broad spectrum MMP inhibitor, GM6001, significantly reduced the migration of cumulus cells in vitro. These data provide evidence that multiple proteases and their inhibitors are expressed in the COCs and play an important role in imparting the migratory phenotype of the COCs at the time of ovulation.
    Keywords:  ADAMTS; cumulus; expansion; granulosa cell; metalloproteinase; migration; oocyte; ovary; plasmin; protease; protease inhibitor
    DOI:  https://doi.org/10.1093/biolre/ioae108
  18. Genetics. 2024 Jul 19. pii: iyae114. [Epub ahead of print]
    ADR-2 regulates fertility and oocyte fate in C. elegans.
    Emily A Erdmann, Melanie Forbes, Margaret Becker, Sarina Perez, Heather A Hundley.
      RNA binding proteins play essential roles in coordinating germline gene expression and development in all organisms. Here, we report that loss of ADR-2, a member of the Adenosine DeAminase acting on RNA (ADAR) family of RNA binding proteins and the sole adenosine-to-inosine RNA editing enzyme in C. elegans, can improve fertility in multiple genetic backgrounds. First, we show that loss of RNA editing by ADR-2 restores normal embryo production to subfertile animals that transgenically express a vitellogenin (yolk protein) fusion to green fluorescent protein. Using this phenotype, a high-throughput screen was designed to identify RNA binding proteins that when depleted yield synthetic phenotypes with loss of adr-2. The screen uncovered a genetic interaction between ADR-2 and SQD-1, a member of the heterogenous nuclear ribonucleoprotein (hnRNP) family of RNA binding proteins. Microscopy, reproductive assays, and high-throughput sequencing reveal that sqd-1 is essential for the onset of oogenesis and oogenic gene expression in young adult animals, and that loss of adr-2 can counteract the effects of loss of sqd-1 on gene expression and rescue the switch from spermatogenesis to oogenesis. Together, these data demonstrate that ADR-2 can contribute to the suppression of fertility and suggest novel roles for both RNA editing-dependent and independent mechanisms in regulating embryogenesis.
    Keywords:  ADAR; RNA editing; dsRBP; germline; hnRNP; inosine; oogenesis
    DOI:  https://doi.org/10.1093/genetics/iyae114
  19. Front Cell Dev Biol. 2024 ;12 1410914
    Mechanism of LncRNA Gm2044 in germ cell development.
    Qinran Zhu, Junpei Sun, Chuangchuang An, Xin Li, Shumin Xu, Yutong He, Xinyi Zhang, Lei Liu, Ke Hu, Meng Liang.
      Germ cell development in mammals is a complex physiological process that involves the proliferation of primordial germ cells, meiosis, and the formation of male and female gametes. Long non-coding RNA (lncRNA) is a type of RNA with more than 200 nucleotides that does not code for proteins. A small number of lncRNAs have been shown to participate in spermatogenesis in the testes and in follicular development in the ovaries, but the role of the vast majority of lncRNAs and their molecular mechanisms still need further study. LncRNA Gm2044 was identified as a differentially expressed lncRNA in mouse spermatogenesis by microarray technology. In mouse testis, lncRNA Gm2044 can act as competing endogenous RNA to regulate SYCP1 expression in GC-2 cells derived from mouse spermatocyte cells, and it can also act as a host gene for miR-202 to regulate RBFOX2 protein expression. In female mouse ovaries, lncRNA Gm2044 regulates 17β-estradiol synthesis through the miRNA-138-5p-Nr5a1 pathway or by interacting with EEF2. In addition, studies suggest that lncRNA Gm2044 is also involved in the progression of reproductive system diseases such as male nonobstructive azoospermia. Here, we summarize the roles and molecular mechanisms of lncRNA Gm2044 in male and female gametogenesis and its potential role in some infertility disorders.
    Keywords:  estrogen; lncRNA; miRNA; ovaries; spermatogenesis
    DOI:  https://doi.org/10.3389/fcell.2024.1410914
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