bims-cebooc Biomed News
on Cell biology of oocytes
Issue of 2024–09–29
eleven papers selected by
Gabriele Zaffagnini, Centre for Genomic Regulation



  1. Cell. 2024 Sep 18. pii: S0092-8674(24)00977-2. [Epub ahead of print]
      Many mammals can temporally uncouple conception from parturition by pacing down their development around the blastocyst stage. In mice, this dormant state is achieved by decreasing the activity of the growth-regulating mTOR signaling pathway. It is unknown whether this ability is conserved in mammals in general and in humans in particular. Here, we show that decreasing the activity of the mTOR signaling pathway induces human pluripotent stem cells (hPSCs) and blastoids to enter a dormant state with limited proliferation, developmental progression, and capacity to attach to endometrial cells. These in vitro assays show that, similar to other species, the ability to enter dormancy is active in human cells around the blastocyst stage and is reversible at both functional and molecular levels. The pacing of human blastocyst development has potential implications for reproductive therapies.
    Keywords:  blastoid; development; diapause; dormancy; human; mTOR; pluripotent stem cells
    DOI:  https://doi.org/10.1016/j.cell.2024.08.048
  2. Sci Adv. 2024 Sep 27. 10(39): eadq7540
      During eukaryotic cell division, a microtubule-based structure called the spindle exerts forces on chromosomes. The best-studied spindle forces, including those responsible for the separation of sister chromatids, are directed parallel to the spindle's long axis. By contrast, little is known about forces perpendicular to the spindle axis, which determine the metaphase plate configuration and thus the location of chromosomes in the subsequent nucleus. Using live-cell microscopy, we find that metaphase chromosomes are spatially anti-correlated in mouse oocyte spindles, evidence of previously unknown long-range forces acting perpendicular to the spindle axis. We explain this observation by showing that the spindle's microtubule network behaves as a nematic liquid crystal and that deformation of the nematic field around embedded chromosomes causes long-range repulsion between them.
    DOI:  https://doi.org/10.1126/sciadv.adq7540
  3. Dev Biol. 2024 Sep 19. pii: S0012-1606(24)00234-3. [Epub ahead of print]517 55-72
      Immature oocytes enclosed in primordial follicles stored in female ovaries are under constant threat of DNA damage induced by endogenous and exogenous factors. Checkpoint kinase 2 (CHEK2) is a key mediator of the DNA damage response (DDR) in all cells. Genetic studies have shown that CHEK2 and its downstream targets, p53, and TAp63, regulate primordial follicle elimination in response to DNA damage. However, the mechanism leading to their demise is still poorly characterized. Single-cell and bulk RNA sequencing were used to determine the DDR in wild-type and Chek2-deficient ovaries. A low but oocyte-lethal dose of ionizing radiation induces ovarian DDR that is solely dependent on CHEK2. DNA damage activates multiple response pathways related to apoptosis, p53, interferon signaling, inflammation, cell adhesion, and intercellular communication. These pathways are differentially employed by different ovarian cell types, with oocytes disproportionately affected by radiation. Novel genes and pathways are induced by radiation specifically in oocytes, shedding light on their sensitivity to DNA damage, and implicating a coordinated response between oocytes and pregranulosa cells within the follicle. These findings provide a foundation for future studies on the specific mechanisms regulating oocyte survival in the context of aging, therapeutic and environmental genotoxic exposures.
    Keywords:  CHEK2; DNA damage response; Oocyte; Ovary; Single-cell transcriptomics
    DOI:  https://doi.org/10.1016/j.ydbio.2024.09.007
  4. bioRxiv. 2024 Sep 11. pii: 2024.09.11.612465. [Epub ahead of print]
      Microtubule (MT) regulation is essential for oocyte development. In Drosophila , MT stability, polarity, abundance, and orientation undergo dynamic changes across developmental stages. In our effort to identify novel microtubule-associated proteins (MAPs) that regulate MTs in the Drosophila ovary, we identified a previously uncharacterized gene, CG18190, encoding a novel MT end-binding (EB) protein, which we propose to name EB-SUN. We show that EB-SUN colocalizes with EB1 at growing microtubule plus-ends in Drosophila S2 cells. Tissue-specific and developmental expression profiles from Paralog Explorer reveal that EB-SUN is predominantly expressed in the ovary and early embryos, while EB1 is ubiquitously expressed. Furthermore, as early as oocyte determination, EB-SUN comets are highly concentrated in oocytes during oogenesis. EB-SUN knockout (KO) results in a decrease in MT density at the onset of mid-oogenesis (Stage 7) and delays oocyte growth during late mid-oogenesis (Stage 9). Combining EB-SUN KO with EB1 knockdown (KD) in germ cells significantly further reduced MT density at Stage 7. Notably, all eggs from EB-SUN KO/EB1 KD females fail to hatch, unlike single gene depletion, suggesting a functional redundancy between these two EB proteins during embryogenesis. Our findings indicate that EB-SUN and EB1 play distinct roles during early embryogenesis.
    Significance Statement: Our study identified a novel microtubule end-binding (EB) protein, which is highly expressed in the Drosophila ovary, and we propose to name it EB-SUN. We demonstrate the functional redundancy of EB-SUN and EB1 during oocyte development, while highlighting their distinct roles in early embryogenesis. Given the high conservation of MT-dependent mechanisms in oogenesis and EB proteins across species, these findings provide insights into the differential regulation and tissue-specific functions of the EB family, using Drosophila as a model system, potentially benefiting future research on MT regulation in higher organisms.
    DOI:  https://doi.org/10.1101/2024.09.11.612465
  5. bioRxiv. 2024 Sep 12. pii: 2024.09.10.612307. [Epub ahead of print]
      Transposable elements (TEs) pose a threat to genome integrity, and the piRNA pathway in animal gonads plays a crucial role in silencing TE activity. While the transcriptional regulation of the piRNA pathway components in germ cells has been documented in mice and flies, the mechanisms orchestrating the transcriptional program of the somatic piRNA pathway in Drosophila ovaries remains unresolved. Here, we demonstrate that Traffic jam (Tj), an orthologue of a large Maf transcription factor in mammals, is a master regulator of the piRNA pathway in ovarian somatic cells, playing a crucial role in maintaining TE silencing and genomic integrity in somatic tissues. We show that Tj directly binds to the promoters of somatic-enriched piRNA factors such as fs(1)Yb , nxf2 , panx , and armi , as well as the flamenco piRNA cluster, a major locus for TE silencing in somatic cells. Depletion of Tj in somatic follicle cells results in a significant downregulation of these piRNA factors, a complete loss of flam expression and de-repression of gypsy -family TEs, which have gained the ability to activate in ovarian somatic cells allowing them to infect germ cells and be transmitted to future generations. We have identified an enhancer carrying Tj binding motifs located downstream of the flam promoter that is essential for robust and tissue-specific flam expression in somatic follicle cells of the adult ovary. This work uncovers a previously unappreciated layer of transcriptional regulation of the piRNA pathway, and we propose that the arms race between the host and TEs has driven the evolution of promoters in piRNA genes and clusters to respond to a unique transcription factor thereby ensuring efficient silencing of gypsy -family TEs.
    Highlights: Traffic jam (Tj) acts as a master regulator of the somatic piRNA pathway in Drosophila . Tj directly controls the expression of the flamenco piRNA cluster, crucial for transposon silencing. Tj regulates a network of piRNA pathway genes, mirroring the gene-regulatory mechanism of A-MYB in the mouse testis.Cis-regulatory elements with Tj motifs are arranged in a palindromic sequence.
    DOI:  https://doi.org/10.1101/2024.09.10.612307
  6. Cell Death Differ. 2024 Sep 23.
      Aneuploidy, the presence of a chromosomal anomaly, is a major cause of spontaneous abortions and recurrent pregnancy loss in humans. However, the underlying molecular mechanisms still remain poorly understood. Here, we report that ARHGAP26, a putative tumor suppressor gene, is a newly identified regulator of oocyte quality to maintain mitochondrial integrity and chromosome euploidy, thus ensuring normal embryonic development and fertility. Taking advantage of knockout mouse model, we revealed that genetic ablation of Arhgap26 caused the oocyte death at GV stage due to the mitochondrial dysfunction-induced ROS accumulation. Lack of Arhgap26 also impaired both in vitro and in vivo maturation of survived oocytes which results in maturation arrest and aneuploidy, and consequently leading to early embryonic development defects and subfertility. These observations were further verified by transcriptome analysis. Mechanistically, we discovered that Arhgap26 interacted with Cofilin1 to maintain the mitochondrial integrity by regulating Drp1 dynamics, and restoration of Arhgap26 protein level recovered the quality of Arhgap26-null oocytes. Importantly, we found an ARHGAP26 mutation in a patient with history of recurrent miscarriage by chromosomal microarray analysis. Altogether, our findings uncover a novel function of ARHGAP26 in the oocyte quality control and prevention of aneuploidy and provide a potential treatment strategy for infertile women caused by ARHGAP26 mutation.
    DOI:  https://doi.org/10.1038/s41418-024-01384-5
  7. bioRxiv. 2024 Sep 15. pii: 2024.09.14.613089. [Epub ahead of print]
      Chromosomal linkages formed through crossover recombination are essential for accurate segregation of homologous chromosomes during meiosis 1 . DNA events of recombination are spatially and functionally linked to structural components of meiotic chromosomes 2 . Imperatively, biased resolution of double-Holliday junction (dHJ) intermediates into crossovers 3,4 occurs within the synaptonemal complex (SC), the meiosis-specific structure that mediates homolog synapsis during the pachytene stage 5,6 . However, the SC's role in crossing over remains unclear. Here we show that SC promotes crossover-specific resolution by protecting dHJs from unscheduled and aberrant resolution. When key SC components are conditionally inactivated during pachytene, dHJs are resolved into noncrossover products by Sgs1-Top3-Rmi1 (STR), the yeast ortholog of the human BLM complex 7 . Cohesin, the core component of SC lateral elements, plays a primary role in chromatin organization and is required to maintain both SCs and crossover recombination complexes (CRCs) during pachytene. SC central region component Zip1 is required to maintain CRCs even when dHJs are stabilized by inactivating STR. Reciprocally, SC stability requires continuous presence of CRCs, an unanticipated interdependence with important implications for SC dynamics. In conclusion, through hierarchical and interdependent functions of its key components, the SC enables crossover-specific dHJ resolution and thereby ensures the linkage and segregation of homologous chromosomes.
    DOI:  https://doi.org/10.1101/2024.09.14.613089
  8. Cells. 2024 Sep 22. pii: 1592. [Epub ahead of print]13(18):
      The field of reproductive biology has made significant progress in recent years, identifying specific molecular players that influence oocyte development and function. Among them, sirtuin 3 (SIRT3) has attracted particular attention for its central role in mediating mitochondrial function and cellular stress responses in oocytes. So far, studies have demonstrated that the knockdown of SIRT3 leads to a decrease in blastocyst formation and an increase in oxidative stress within an embryo, underscoring the importance of SIRT3 in maintaining the cellular redox balance critical for embryonic survival and growth. Furthermore, the literature reveals specific signaling pathways, such as the SIRT3- Glycogen synthase kinase-3 beta (GSK3β) deacetylation pathway, crucial for mitigating oxidative stress-related anomalies in oocyte meiosis, particularly under conditions like maternal diabetes. Overall, the emerging role of SIRT3 in regulating oocyte mitochondrial function and development highlights the critical importance of understanding the intricate connections between cellular metabolism, stress response pathways, and overall reproductive health and function. This knowledge could lead to the development of novel strategies to support oocyte quality and fertility, with far-reaching implications for assisted reproductive technologies and women's healthcare. This commentary aims to provide an overview of the importance of SIRT3 in oocytes by synthesizing results from a multitude of studies. The aim is to elucidate the role of SIRT3 in oocyte development, maturation, and aging and to identify areas where further research is needed.
    Keywords:  SIRT3; aging; egg; embryo; mitochondria; oocyte; reproductive aging; sirtuin 3
    DOI:  https://doi.org/10.3390/cells13181592
  9. Reproduction. 2024 Sep 01. pii: REP-24-0087. [Epub ahead of print]
      Thousands of genes are activated in late 2-cell embryos, which means that numerous pre-mRNAs are generated during this time. These pre-mRNAs must be accurately spliced to ensure that the mature mRNAs are translated to functional proteins. However, little is known about the roles of pre-mRNA splicing and cellular factors modulating pre-mRNA splicing during early embryonic development. Here, we report that downregulation of SON, a large Ser/Arg (SR)-related protein, reduced embryonic development and caused deficient blastomere cleavage. These embryonic developmental defects result from dysregulated nuclear speckle organization and pre-mRNA splicing of a set of cell cycle-related genes. Furthermore, SON downregulation disrupted the transcriptome (2128 upregulated and 1399 downregulated) in 4-cell embryos. Increased H3K4me3, H3K9me3 and H3K27me3 levels were detected in 4-cell embryos after SON downregulation. Taken together, these results demonstrate that accurate pre-mRNA splicing is essential for early embryonic development and that SON plays important roles in nuclear speckle organization, pre-mRNA splicing, transcriptome establishment and histone methylation reprogramming during early embryonic development.
    DOI:  https://doi.org/10.1530/REP-24-0087
  10. Cell Rep. 2024 Sep 25. pii: S2211-1247(24)01132-X. [Epub ahead of print]43(10): 114781
      Animal development is dictated by the selective and timely decay of mRNAs in developmental transitions, but the impact of mRNA decapping scaffold proteins in development is unclear. This study unveils the roles and interactions of the DCAP-2 decapping scaffolds EDC-3 and EDC-4 in the embryonic development of C. elegans. EDC-3 facilitates the timely removal of specific embryonic mRNAs, including cgh-1, car-1, and ifet-1 by reducing their expression and preventing excessive accumulation of DCAP-2 condensates in somatic cells. We further uncover a role for EDC-3 in defining the boundaries between P bodies, germ granules, and stress granules. Finally, we show that EDC-4 counteracts EDC-3 and engenders the assembly of DCAP-2 with the GID (CTLH) complex, a ubiquitin ligase involved in maternal-to-zygotic transition (MZT). Our findings support a model where multiple RNA decay mechanisms temporally clear maternal and zygotic mRNAs throughout embryonic development.
    Keywords:  C. elegans;; CP: Developmental biology; CP: Molecular biology; DCAP-2/Dcp2; EDC-3; EDC-4; GID/CTLH complex; IFET-1/CAR-1/CGH-1 complex; P bodies; decapping; germ granules; mRNA decay; microRNA
    DOI:  https://doi.org/10.1016/j.celrep.2024.114781
  11. Aging Dis. 2024 Sep 04.
      The ovary experiences an age-dependent decline starting during the fourth decade of life. Ovarian aging is the predominant factor driving female reproductive aging. Modern trend to postpone childbearing age contributes to reduced fertility and natality worldwide. Recently, the beneficial role of NAD+ precursors on the maintenance of oocyte competence and female fertility affected by aging has emerged. Nevertheless, age-related changes in NAD+ regulatory network have not been investigated so far. In this context, our goal was to investigate changes induced by the aging process in the expression level of genes participating in NAD+ biosynthetic and NAD+ consuming pathways and in the cellular bioenergetics in the mouse oocyte. From Ingenuity Pathway Analysis (IPA) it emerged that aging caused the downregulation of all cellular pathways for NAD+ synthesis (Kynurenine pathway, Preiss-Handler pathway and NAD+ salvage pathway) and deeply influenced the activity of NAD+-dependent enzymes, i.e. PARPs and SIRTs, with effects on many cellular functions including compromised ROS detoxification. Considering that NAMPT, the rate-limiting enzyme of NAD+ salvage pathway, was deregulated, aged oocytes were matured in the presence of P7C3, NAMPT activator. P7C3 improved spindle assembly and mitochondrial bioenergetics and reduced mitochondrial proton leak. Moreover, P7C3 influenced gene expression of NAD+ regulatory network, with Sirt1 as the central node of IPA-interfered target gene network. Finally, P7C3 effectively counteracted oocyte alterations induced by exposure to oxidative stress. Our study contributes to establish effective NAD+ boosting interventions to alleviate the effects of advanced maternal age on fertility and explore their potential in redox-related fertility disorders.
    DOI:  https://doi.org/10.14336/AD.2024.0241