bims-cebooc Biomed News
on Cell biology of oocytes
Issue of 2025–02–16
eleven papers selected by
Gabriele Zaffagnini, Universität zu Köln
  1. UBE2D3 functions in mouse oocyte meiotic maturation.
  2. Adaptive evolution of CENP-T modulates centromere binding.
  3. Phenogenetics of cortical granule dynamics during zebrafish oocyte-to-embryo transition.
  4. Acetylation at lysine 27 on maternal H3.3 regulates minor zygotic genome activation.
  5. Relationship between chromatin configuration and maturation ability of rat oocytes in vitro and in vivo.
  6. A multi-omic single-cell landscape of the aging mouse ovary.
  7. The spatiotemporal distribution of LIN-5/NuMA regulates spindle orientation in the C. elegans germ line.
  8. Granulosa cell expression of Fos is critical for regulating ovulatory gene expressions in the mouse ovary.
  9. Stochastic Analysis of Human Ovarian Aging and Menopause Timing.
  10. Pathogenic mechanism of abnormal expression of HDAC3 in ovulatory granulosa cells inducing oocyte maturation disorder and its application in IVM.
  11. Identification of FSH-regulated and estrous stage-specific transcriptional networks in mouse ovaries.
  1. FASEB J. 2025 Feb 15. 39(3): e70375
    UBE2D3 functions in mouse oocyte meiotic maturation.
    Guorui Zhang, Na Zhang, Bin Zhang, Yilong Zhao, Qiang Wang, Longsen Han.
      Ubiquitin-mediated proteolysis plays a critical role in meiotic cell-cycle regulation and must be tightly controlled to achieve correct chromosome segregation. While the role of E2 ubiquitin-conjugating enzymes in mitosis is well-documented, their functions in oocyte meiosis remain largely unexplored. In this study, we identified UBE2D3 as the most highly expressed E2 enzyme in mouse oocytes, which is essential for proper meiotic division. UBE2D3 depletion caused (metaphase I) MI arrest and Cyclin B1 accumulation, whereas its overexpression led to reduced Cyclin B1 levels, kinetochore-microtubule (K-MT) mis-attachments, spindle assembly checkpoint (SAC) dysfunction, and increased aneuploidy. Notably, UBE2D3 upregulation in oocytes from aged mice contributed to age-related meiotic defects, which were partially reversed by UBE2D3 knockdown or Cyclin B1 overexpression. This study underscores the importance of the UBE2D3-Cyclin B1 axis in maintaining meiotic fidelity and highlights its potential as a therapeutic target for improving oocyte quality and fertility in aged females.
    Keywords:  UBE2D3; aneuploidy; maternal age; oocyte
    DOI:  https://doi.org/10.1096/fj.202403033R
  2. Curr Biol. 2025 Feb 10. pii: S0960-9822(25)00046-6. [Epub ahead of print]
    Adaptive evolution of CENP-T modulates centromere binding.
    Damian Dudka, Alexandra L Nguyen, Katelyn G Boese, Océane Marescal, R Brian Akins, Ben E Black, Iain M Cheeseman, Michael A Lampson.
      Centromeric DNA and proteins evolve rapidly despite conserved function in mediating kinetochore-microtubule attachments during cell division. This paradox is explained by selfish DNA sequences preferentially binding centromeric proteins to disrupt attachments and bias their segregation into the egg (drive) during female meiosis. Adaptive centromeric protein evolution is predicted to prevent preferential binding to these sequences and suppress drive. Here, we test this prediction by defining the impact of adaptive evolution of the DNA-binding histone fold domain of CENP-T, a major link between centromeric DNA and microtubules. We reversed adaptive changes by creating chimeric variants of mouse CENP-T with the histone fold domain from closely related species, expressed exogenously in mouse oocytes or in a transgenic mouse model. We show that adaptive evolution of mouse CENP-T reduced centromere binding, which supports robust female gametogenesis. However, this innovation is independent of the centromeric DNA sequence, as shown by comparing the binding of divergent CENP-T variants to distinct centromere satellite arrays in mouse oocytes and in somatic cells from other species. Overall, our findings support a model in which selfish sequences drive to fixation, disrupting attachments of all centromeres to the spindle. DNA sequence-specific innovations are not needed to mitigate fitness costs in this model, so centromeric proteins adapt by modulating their binding to all centromeres in the aftermath of drive.
    Keywords:  CENP-T; adaptive evolution; centromere; centromere drive; female meiosis; mouse oocytes
    DOI:  https://doi.org/10.1016/j.cub.2025.01.017
  3. Front Cell Dev Biol. 2025 ;13 1514461
    Phenogenetics of cortical granule dynamics during zebrafish oocyte-to-embryo transition.
    Priscila García-Castro, Isabella Giambó-Falian, Ingrid Carvacho, Ricardo Fuentes.
      Fertilization is a critical process in sexual reproduction that involves the fusion of a capacitated sperm with a mature oocyte to form a zygote. Polyspermy, the fertilization of an oocyte by multiple sperm, leads to polyploidy and embryo lethality. Mammalian and non-mammalian oocytes have evolved mechanisms to prevent polyspermy, including fast and slow blocks. The fast block comprises membrane depolarization post-sperm fusion, temporarily preventing additional sperm fusion. The slow block, triggered by cortical granule (CG) exocytosis, involves the release of proteins that modify the zona pellucida to form a permanent barrier, avoiding the fertilization by additional sperm. The evidence shows that immature oocytes often fail to prevent polyspermy due to ineffective CG exocytosis, attributed to impaired intracellular calcium increases, lower content of this ion, and incomplete CG migration. The study of how genetic variations lead to observable phenotypes (phenogenetics) during the oocyte-to-embryo transition, have identified several maternal-effect genes in zebrafish involved in CG behavior. These genes regulate various stages of CG biology, including biosynthesis, maturation, and exocytosis. Mutations in these genes disrupt these processes, highlighting the maternal genetic control over CG properties. Zebrafish has emerged as a pivotal model for understanding the evolving genetic regulation and molecular mechanisms underlying CG biology, providing valuable insights into fertility and early embryonic development.
    Keywords:  cortical granule dynamics; fertilization; oocyte maturation; polyspermy; zebrafish
    DOI:  https://doi.org/10.3389/fcell.2025.1514461
  4. Cell Rep. 2025 Jan 28. pii: S2211-1247(24)01499-2. [Epub ahead of print]44(1): 115148
    Acetylation at lysine 27 on maternal H3.3 regulates minor zygotic genome activation.
    Jiaming Zhang, Xuanwen Li, Qi Zhao, Jingzhang Ji, Hongdi Cui, Weibo Hou, Xinyu Wang, Entong Song, Songling Xiao, Shukuan Ling, Shaorong Gao, Xiaoyu Liu, Duancheng Wen, Qingran Kong.
      Zygotic genome activation (ZGA) initiates transcription in early embryogenesis and requires extensive chromatin remodeling, including rapid incorporation of the histone variant H3.3. The distinct sources of H3.3 from paternal and maternal alleles (paH3.3 and maH3.3) complicate tracking their individual contributions. Here, using an H3.3B-hemagglutinin (HA)-tagged mouse model, we profile the temporal dynamics of paH3.3 and maH3.3, revealing a unique pattern of maH3.3 enrichment at the promoter regions from zygotes to 2-cell embryos, highlighting the crucial role of maternally stored H3.3 mRNAs and proteins (mH3.3) in pre-implantation development. Knockdown of mH3.3 compromises cleavage and minor ZGA. Mechanistically, mH3.3 facilitates minor ZGA through H3.3S31ph-dependent H3K27ac deposition. Profiling of H3.3 landscape in parthenogenetic (PG) and androgenetic (AG) embryos highlights the role of mH3.3 in remodeling the paternal genome by establishing H3K27ac. These findings demonstrate that mH3.3-mediated parental chromatin reprogramming is essential for orchestrating minor ZGA.
    Keywords:  CP: Developmental biology; CP: Molecular biology; early embryonic development; epigenetic reprogramming; histone variants; maternal H3.3; zygotic genome activation
    DOI:  https://doi.org/10.1016/j.celrep.2024.115148
  5. PLoS One. 2025 ;20(2): e0312241
    Relationship between chromatin configuration and maturation ability of rat oocytes in vitro and in vivo.
    Zhaoqing Gong, Yujie Wang, Jiayi Tang, Yang Xu, Hongkai Wang, Yimiao Zhang, Lixin Xiong, Changzheng Sun, Yiyang Li, Yan Yang, Minhua Yao, Heng Cai, Zengshuo Man, Siyu Xuan, Yangyang Tang, Ziao Zhao, Jiaxin Sun, Dongwei Liu, Yanping Su, Xinghua Xu, Mingjiu Luo, Hongshu Sui.
       PURPOSE: Embryo engineering requires a large number of oocytes, which undergo in vitro maturation (IVM). Understanding how to select the best quality oocytes is key to improving IVM efficiency. Oocytes have different germinal vesicle (GV) chromatin configurations, which may explain the heterogeneity in oocyte quality during IVM. However, no reports have categorized, the chromatin configuration of rat GVs or evaluated, the association between the chromatin configuration and oocytes development.
    METHODS: The GV chromatin configuration of rat oocytes was divided into seven types according to the degree of chromatin compaction: non-surrounded nucleolus (NSN), prematurely condensed NSN, partly NSN, partly surrounded nucleolus (SN-1), SN-1, condensed SN-1, and aggregated (SN-2). The chromatin configuration distribution was compared during the different stages of oocyte growth and maturation. We also analyzed the changes in the chromatin configuration at different GV stages during IVM. Moreover, the factors affecting the chromatin configuration were analyzed.
    RESULTS: The SN-2 configuration increased with rat oocyte growth and maturation, suggesting that SN-2 facilitates oocyte development. RNA transcription activity in rat oocyte GVs was inversely correlated with oocyte IVM.
    CONCLUSIONS: The SN-2 chromatin configuration was related to rat oocyte growth and maturation. RNA transcription activity in rat oocytes in the GV stage was inversely correlated with oocyte maturation.
    DOI:  https://doi.org/10.1371/journal.pone.0312241
  6. Geroscience. 2025 Feb 11.
    A multi-omic single-cell landscape of the aging mouse ovary.
    Jian Zhang, Shunze Jia, Zehua Zheng, Lanrui Cao, Jingyi Zhou, Xudong Fu.
      The ovary is one of the first organs in humans to exhibit age-related functional impairments. As an organ composed of diverse heterogeneous cell types, the ovary exhibits cell-type-specific changes during the aging process, ultimately leading to a decline in female fertility. Investigating the molecular mechanisms of ovarian aging is crucial for understanding age-related fertility dysfunction in females. In this study, we combine scRNA-seq and scATAC-seq from mouse young/aged ovaries to characterize molecular features during ovarian aging. Using the single-cell multi-omic data, we revealed the cell-type-specific transcriptional changes during the aging process in seven major ovarian cell types and identified the cis/trans-regulatory elements governing these transcriptional changes. Specifically, we uncovered the transcriptional alterations of TGF-beta signaling in mesenchymal cells and endoplasmic reticulum stress in granulosa cells of aged mouse ovaries and further identified the potential corresponding cis/trans-regulatory elements. These molecular alterations may contribute to aging-induced functional impairments in mouse ovaries. In summary, this work provides transcriptome and chromatin accessibility landscape of ovarian aging in mice, which serve as a resource for identifying the cell-type-specific molecular mechanisms underlying ovarian aging, aiding in the identification of potential diagnostic biomarkers and treatment strategies.
    Keywords:  Apoptosis; ER stress; Fibrosis; Ovarian aging; TGF beta 2
    DOI:  https://doi.org/10.1007/s11357-025-01556-2
  7. Cell Rep. 2025 Feb 12. pii: S2211-1247(25)00067-1. [Epub ahead of print]44(2): 115296
    The spatiotemporal distribution of LIN-5/NuMA regulates spindle orientation in the C. elegans germ line.
    Réda M Zellag, Vincent Poupart, Takefumi Negishi, Jean-Claude Labbé, Abigail R Gerhold.
      Mitotic spindle orientation contributes to tissue organization and shape by setting the cell division plane. How spindle orientation is coupled to diverse tissue architectures is incompletely understood. The C. elegans gonad is a tube-shaped organ with germ cells forming a circumferential monolayer around a common cytoplasmic lumen. How this organization is maintained during development is unclear, as germ cells lack the canonical cell-cell junctions that ensure spindle orientation in other tissue types. Here, we show that the microtubule force generator dynein and its conserved regulator LIN-5/NuMA regulate germ cell spindle orientation and are required for germline tissue organization. We uncover a cyclic, polarized pattern of LIN-5/NuMA cortical localization that predicts centrosome positioning throughout the cell cycle, providing a means to align spindle orientation with the tissue plane. This work reveals a new mechanism by which oriented cell division can be achieved to maintain tissue organization during animal development.
    Keywords:  CP: Cell biology; CP: Developmental biology; Caenorhabditis elegans; LIN-5/NuMA; dynein; germ cells; germline development; gonad explants; in situ live-cell imaging; mitotic spindle orientation; oriented cell division; tissue organization
    DOI:  https://doi.org/10.1016/j.celrep.2025.115296
  8. FASEB J. 2025 Feb 28. 39(4): e70388
    Granulosa cell expression of Fos is critical for regulating ovulatory gene expressions in the mouse ovary.
    Jacqueline Southall, Shawn Park, Yohan Choi, Hayce Jeon, Chemyong Ko, Misung Jo.
      A previous study showed that female Fos null mice fail to ovulate even when given gonadotropins, suggesting that ovarian expression of Fos is critical for successful ovulation. However, the expression of FOS and function of FOS have not been determined in the mouse ovary. FOS, a member of the Fos family (Fos, Fosb, Fosl1, and Fosl2), functions as a transcription factor by forming a heterodimer complex with a member of Jun family (Jun, Junb, and Jund). This study demonstrated rapid increases in Fos, along with other Fos and Jun family members, after hCG administration in the ovary of immature PMSG-primed mice and after the LH surge in naturally cycling animals. ChIP-seq analysis identified 1965 FOS-binding genes in granulosa cells collected at 3 h post-hCG, including Pgr, Ptgs2, Tnfiap6, and Edn2, genes known to be involved in the ovulatory process. When super-ovulation was induced, the number of oocytes released was significantly reduced in Esr2cre/+-driven granulosa cell-specific Fos knockout (gcFosKO) mice. This reduction was accompanied by lower expressions of Pgr, Ptgs2, Ptgs1, and Edn2 in preovulatory follicles of gcFosKO mice compared to those in control littermates. In addition, gcFosKO mice showed a trend toward a decreased average litter size. Together, the present study indicates that the preovulatory induction of Fos expression is crucial for increasing the expression of key ovulatory genes, yet the role of FOS may be partially substituted by other Fos and Jun family members induced in the preovulatory follicle in the gcFosKO mouse ovary.
    Keywords:  FOS; fertility; granulosa cells; ovary; ovulation
    DOI:  https://doi.org/10.1096/fj.202402867R
  9. Biophys J. 2025 Feb 10. pii: S0006-3495(25)00061-X. [Epub ahead of print]
    Stochastic Analysis of Human Ovarian Aging and Menopause Timing.
    Anupam Mondal, Evelina Tcherniak, Anatoly B Kolomeisky.
      Menopause marks a critically important biological event that ends a woman's fertility. It is a result of ovarian aging and depletion of ovarian reserve. While many aspects of these processes are now well understood, the overall dynamic picture remains unclear. Here, we present a novel theoretical framework to analyze human ovarian aging dynamics and menopause timing. Our method is based on stochastic analysis of underlying processes stimulated by observing follicles sequentially transitioning between different stages during ovulation. This allows us to obtain a fully quantitative description of ovarian aging and menopause timing consistent with available experimental observations. Our model accurately predicts the average age of menopause across geographically diverse human populations. Theoretical analysis suggests a universal relation between the initial follicle reserve, the depletion rates, and the threshold that triggers menopause. In addition, it is found that the distributions of menopause times are quite narrow, and it is proposed that this might be a result of a precise regulation due to synchronization of transitions between different stages of follicles. Our theoretical approach not only quantitatively explains the dynamics of human ovarian aging and menopause timing, but also provides important insights into individual variability in ovarian aging. It can be used as a powerful tool for predicting menopause timing and for investigating complex processes of reproductive aging.
    DOI:  https://doi.org/10.1016/j.bpj.2025.02.004
  10. J Biol Chem. 2025 Feb 10. pii: S0021-9258(25)00135-8. [Epub ahead of print] 108287
    Pathogenic mechanism of abnormal expression of HDAC3 in ovulatory granulosa cells inducing oocyte maturation disorder and its application in IVM.
    Huarong Wang, Han Cai, Meiling Zhang, Chuanhui Guo, Peike Wang, Na Deng, Haili Bao, Fanjing Meng, Qing Li, Shuiying Ma, Shuangbo Kong, Wenbo Deng, Hua Zhang, Guoliang Xia, Fengchao Wang, Chao Wang, Haibin Wang.
      Female reproductive health is troubled by oocyte maturation disorder. In mammals, granulosa cells (GCs) mediate LH action on oocyte maturation and ovulation. However, the pathogenesis of disordered GCs in oocyte maturation arrest is rarely studied. Our previous study has showed that HDAC3 in GCs was decreased by LH at physiological condition. Here, we observed significantly elevated HDAC3 levels in GCs from patients with oocyte maturation disorder following LH treatment compared to those with normal oocyte maturation. To clarify whether abnormally high levels of HDAC3 in ovulatory GCs resulted in female infertility, a mice model of GC-conditional overexpression of Hdac3 was constructed. The results showed that abnormally high levels of HDAC3 in ovulatory GCs inhibited LH induction on oocyte maturation and ovulation, resulting in female infertility. Further, in GCs with abnormal high levels of HDAC3, the upregulation of oocyte maturation-related genes induced by LH was attenuated by HDAC3 through a reduction in H3K14ac levels in the promoter regions, implying that the action of LH in GCs was largely negatively controlled by HDAC3. Applying HDAC3 inhibitors enhanced the expression of multiple genes associated with oocyte maturation in GCs from clinical patients, ultimately improving both the oocyte maturation rate and developmental quality, as demonstrated by a higher blastocyst development rate. The findings contribute to both enrich understanding upon the pathological mechanisms and supply optimal treatment strategies for patients with oocyte maturation disorder.
    Keywords:  Granulosa cell; HDAC3; LH; Oocyte maturation
    DOI:  https://doi.org/10.1016/j.jbc.2025.108287
  11. Proc Natl Acad Sci U S A. 2025 Feb 18. 122(7): e2411977122
    Identification of FSH-regulated and estrous stage-specific transcriptional networks in mouse ovaries.
    Kathryn Walters, Amber Baldwin, Zhenghui Liu, Mark Larsen, Neelanjan Mukherjee, T Rajendra Kumar.
      Follicle-stimulating hormone (FSH) acts by binding to FSHRs expressed on ovarian granulosa cells and produces estradiol. FSH is essential for female fertility because mice lacking FSH (Fshb KO) are anestrous and infertile. Although several in vitro cell culture and ex vivo approaches combined with pharmacological hormone treatment were used to identify FSH-regulated genes, how FSH orchestrates ovarian gene networks in vivo has not been investigated. Whether FSH-regulated genes display estrous stage-specific expression changes has also not been studied. Here, we functionally rescued Fshb null mice with a gonadotrope-targeted HFSHB transgene and performed RNA-Seq analysis on ovarian RNAs obtained from FSH-intact (WT), FSH-deficient (Fshb KO), and FSH-rescue (HFSHB+ rescue) mice. By comparing WT vs. Fshb KO and Fshb KO vs. HFSHB+ rescue ovarian gene expression datasets, we identified FSH-responsive genes in vivo. Cross interrogation of these datasets further allowed us to identify several transcription factors (TFs) and RNA-binding proteins specific to FSH-regulated genes. In an independent set of experiments, we performed RNA-Seq analysis on ovarian RNAs from mice in diestrous (DE), proestrous (PE), and estrous (E) and identified estrous stage-specific ovarian gene expression patterns. Interestingly, many of the FSH-regulated TFs themselves were estrous-stage specifically expressed. We found that ESR2 and GATA6, two known FSH-responsive TFs, and their target genes are reciprocally regulated with distinct patterns of expression in estrous stages. Together, our in vivo models and RNA-Seq analyses identify FSH-regulated ovarian genes in specific estrous stages that are under transcriptional and posttranscriptional control.
    Keywords:  FSH; RNA-binding proteins; estrus cycles; ovary; transcription factors
    DOI:  https://doi.org/10.1073/pnas.2411977122
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