bims-cebooc Biomed News
on Cell biology of oocytes
Issue of 2025–04–27
twelve papers selected by
Gabriele Zaffagnini, Universität zu Köln
  1. The establishment of nuclear organization in mouse embryos is orchestrated by multiple epigenetic pathways.
  2. RIF1 controls replication timing in early mouse embryos independently of lamina-associated nuclear organization.
  3. SGO2 does not play an essential role in separase inhibition during meiosis I in mouse oocytes.
  4. The retrotransposon-derived capsid genes PNMA1 and PNMA4 maintain reproductive capacity.
  5. PABPN1 Couples the Polyadenylation and Translation of Maternal Transcripts to Mouse Oocyte Meiotic Maturation.
  6. The adult ovary at single cell resolution: an expert review.
  7. Nuage in color: Systematic protein tagging shows the compositional complexity of germ granules.
  8. Combinatorial tagging generates a multi-purpose knock-in mouse model revealing phase separation-dependent germ granules in RNA homeostasis and germline development.
  9. Telomeres, the nuclear lamina, and membrane remodeling: Orchestrating meiotic chromosome movements.
  10. Three-dimensional genome structures of single mammalian sperm.
  11. Vitellogenin receptor mediates heat adaptability of oocyte development in mud crabs and zebrafish.
  12. A selfish supergene causes meiotic drive through both sexes in Drosophila.
  1. Cell. 2025 Apr 15. pii: S0092-8674(25)00396-4. [Epub ahead of print]
    The establishment of nuclear organization in mouse embryos is orchestrated by multiple epigenetic pathways.
    Mrinmoy Pal, Tamas Schauer, Adam Burton, Tsunetoshi Nakatani, Federico Pecori, Alicia Hernández-Giménez, Iliya Nadelson, Marc A Marti-Renom, Maria-Elena Torres-Padilla.
      The folding of the genome in the 3D nuclear space is fundamental for regulating all DNA-related processes. The association of the genome with the nuclear lamina into lamina-associated domains (LADs) represents the earliest feature of nuclear organization during development. Here, we performed a gain-of-function screen in mouse embryos to obtain mechanistic insights. We find that perturbations impacting histone H3 modifications, heterochromatin, and histone content are crucial for the establishment of nuclear architecture in zygotes and/or 2-cell-stage embryos. Notably, some perturbations exerted differential effects on zygotes versus 2-cell-stage embryos. Moreover, embryos with disrupted LADs can rebuild nuclear architecture at the 2-cell stage, indicating that the initial establishment of LADs in zygotes might be dispensable for early development. Our findings provide valuable insights into the functional interplay between chromatin and structural components of the nucleus that guide genome-lamina interactions during the earliest developmental stages.
    Keywords:  3D genome organization; LAD; MZT; ZGA; epigenetics; mouse embryo; nuclear architecture
    DOI:  https://doi.org/10.1016/j.cell.2025.03.044
  2. Dev Cell. 2025 Apr 16. pii: S1534-5807(25)00179-0. [Epub ahead of print]
    RIF1 controls replication timing in early mouse embryos independently of lamina-associated nuclear organization.
    Tsunetoshi Nakatani, Tamas Schauer, Mrinmoy Pal, Andreas Ettinger, Luis Altamirano-Pacheco, Julia Zorn, David M Gilbert, Maria-Elena Torres-Padilla.
      Cells must duplicate their genome before they divide to ensure equal transmission of genetic information. The genome is replicated with a defined temporal order, replication timing (RT), which is cell-type specific and linked to 3D-genome organization. During mammalian development, RT is initially not well defined and becomes progressively consolidated from the 4-cell stage. However, the molecular regulators are unknown. Here, by combining loss-of-function analysis with genome-wide investigation of RT in mouse embryos, we identify Rap1 interacting factor 1 (RIF1) as a regulator of the progressive consolidation of RT. Embryos without RIF1 show DNA replication features of an early, more totipotent state. RIF1 regulates the progressive stratification of RT values and its depletion leads to global RT changes and a more heterogeneous RT program. Developmental RT changes are disentangled from changes in transcription and nuclear organization, specifically nuclear lamina association. Our work provides molecular understanding of replication and genome organization at the beginning of mammalian development.
    Keywords:  RIF1; early mouse embryos; lamina-associated domains; replication fork speed; replication timing; single-cell Repli-seq
    DOI:  https://doi.org/10.1016/j.devcel.2025.03.016
  3. PLoS Biol. 2025 Apr;23(4): e3003131
    SGO2 does not play an essential role in separase inhibition during meiosis I in mouse oocytes.
    Benjamin Wetherall, David Bulmer, Alexandra Sarginson, Christopher Thomas, Suzanne Madgwick.
      During meiosis I in oocytes, anaphase is triggered by deactivation of cyclin B1-CDK1 and activation of separase. Active separase plays an essential role in cleaving cohesin rings that hold homologous chromosomes together. Critically, separase must be inhibited until all chromosomes are aligned and the cell is prepared for anaphase I. Inhibition can be mediated through the binding of separase to either securin or cyclin B1-CDK1. The relative contribution of each inhibitory pathway varies depending on cell type. Recently, shugoshin-2 (SGO2) has also been shown to inhibit separase in mitotic cells. Here, we used a separase biosensor and perturbed the three inhibitory pathways during meiosis I in mouse oocytes. We show that inhibition mediated by either securin or cyclin B1-CDK1, but not SGO2, is independently sufficient to suppress separase activity. However, when both the securin and cyclin B1-CDK1 inhibitory pathways are perturbed together, separase activity begins prematurely, resulting in gross segregation defects. Furthermore, we characterized SGO2 destruction dynamics and concluded that it is not an essential separase inhibitor in mouse oocytes. The existence of multiple separase inhibitory pathways highlights the critical importance of tightly regulated separase activity during this unique and challenging cell division.
    DOI:  https://doi.org/10.1371/journal.pbio.3003131
  4. Nat Aging. 2025 Apr 22.
    The retrotransposon-derived capsid genes PNMA1 and PNMA4 maintain reproductive capacity.
    Thomas W P Wood, William S Henriques, Harrison B Cullen, Mayra Romero, Cecilia S Blengini, Shreya Sarathy, Julia Sorkin, Hilina Bekele, Chen Jin, Seungsoo Kim, Xifan Wang, Raphaelle Laureau, Alexei Chemiakine, Rishad C Khondker, José V V Isola, Michael B Stout, Vincenzo A Gennarino, Binyam Mogessie, Devanshi Jain, Karen Schindler, Yousin Suh, Blake Wiedenheft, Luke E Berchowitz.
      Almost half of the human genome consists of retrotransposons-'parasitic' sequences that insert themselves into the host genome via an RNA intermediate. Although most of these sequences are silenced or mutationally deactivated, they can present opportunities for evolutionary innovation: mutation of a deteriorating retrotransposon can result in a gene that provides a selective advantage to the host in a process termed 'domestication'1-3. The PNMA family of gag-like capsid genes was domesticated from an ancient vertebrate retrotransposon of the Metaviridae clade at least 100 million years ago4,5. PNMA1 and PNMA4 are positively regulated by the master germ cell transcription factors MYBL1 and STRA8, and their transcripts are bound by the translational regulator DAZL during gametogenesis6. This developmental regulation of PNMA1 and PNMA4 expression in gonadal tissue suggested to us that they might serve a reproductive function. Through the analysis of donated human ovaries, genome-wide association studies (GWASs) and mouse models, we found that PNMA1 and PNMA4 are necessary for the maintenance of a normal reproductive lifespan. These proteins self-assemble into capsid-like structures that exit human cells, and we observed large PNMA4 particles in mouse male gonadal tissue that contain RNA and are consistent with capsid formation.
    DOI:  https://doi.org/10.1038/s43587-025-00852-y
  5. Adv Sci (Weinh). 2025 Apr 23. e2500048
    PABPN1 Couples the Polyadenylation and Translation of Maternal Transcripts to Mouse Oocyte Meiotic Maturation.
    Xing-Xing Dai, Yu-Ke Wu, Shuai-Bo Pi, Feng-Jie Hu, Yun-Wen Wu, Hang Qi, Zhi-Yan Jiang, Long-Wen Zhao, Heng-Yu Fan.
      During oocyte meiosis, maternal transcript polyadenylation is crucial for regulating mRNA stability and translation, which are essential for oocyte maturation. Polyadenylate-binding protein nuclear 1 (PABPN1) plays a key role in regulating mRNA splicing and polyadenylation in somatic cells and growing oocytes. However, its potential function in regulating the meiotic maturation of fully grown oocytes remains unknown. This study reports that selective Pabpn1 knockout in growing mouse oocytes using Zp3-Cre do not affect folliculogenesis but prevented germinal vesicle breakdown in fully grown oocytes, impaired CDK1 activation, and resulted in abnormal spindle formation and chromosome misalignment. The results of poly(A)-inclusive full-length RNA isoform sequencing (PAIso-seq) and transcriptome sequencing revealed that PABPN1 coordinates meiotic maturation-coupled polyadenylation and degradation of maternal mRNAs, which are key factors of maturation-promoting factor (MPF) and deadenylation mediators, such as B-cell translocation gene-4 (BTG4), ensuring proper meiotic progression. The results of rescue experiments indicate these functions of PABPN1 are mediated by its key domains, which interact with poly(A) polymerase and recruit target mRNAs. This study highlighted the physiological importance of cytoplasmic PABPN1 in mammalian oocyte maturation by integrating maternal transcript polyadenylation, translation, and degradation.
    Keywords:  RNA stability; RNA‐binding protein; female fertility; meiosis; oocyte maturation; translation activity
    DOI:  https://doi.org/10.1002/advs.202500048
  6. Am J Obstet Gynecol. 2025 Apr;pii: S0002-9378(24)00650-1. [Epub ahead of print]232(4S): S95.e1-S95.e16
    The adult ovary at single cell resolution: an expert review.
    Ilmatar Rooda, Loren Méar, Jasmin Hassan, Pauliina Damdimopoulou.
      The ovaries play a crucial role in both the endocrine health and fertility of adult women. The fundamental functional units of the ovaries, primordial follicles, form during fetal development and constitute the ovarian reserve. Ovaries age prematurely in comparison to other organs, with the quality of oocytes declining steeply prior to the entire reserve becoming depleted, usually around age 50. Despite the pivotal role of ovaries in women's overall health, surprisingly little is known about the mechanisms controlling follicle dormancy, growth activation, atresia, maturation, and oocyte quality. Understanding ovarian function on a cellular and molecular level is increasingly important for several reasons. First, the global trend of women delaying childbirth creates a growing population of patients wishing to conceive when the quality and quantity of their oocytes are already critically low. Second, conditions affecting the ovaries, such as polycystic ovary syndrome and endometriosis, are widespread, yet diagnosis and treatment still present challenges. Lastly, advancements in cancer therapies have increased the number of cancer survivors who contend with late complications affecting fertility and hormonal balance. Clearly, a better understanding of diseases, aging, and toxicity in ovaries is needed for the development of novel treatments, preventive therapies, and safer pharmaceuticals. Human ovaries are notoriously difficult to obtain for research due to their pivotal role in women's health, and the highly heterogeneous distribution of follicles within the tissue combined with monthly cyclical changes present further challenges. Single-cell profiling techniques are creating new opportunities, enabling the characterization of small amounts of tissue with unprecedented resolution. Here, we review the literature on single-cell characterization of adult, reproductive-age ovaries. The majority of the 46 identified studies have focused on oocytes discarded during assisted reproduction, with only a handful focusing on ovarian tissue. The overwhelming focus of the studies is on follicles and oocytes, although the somatic cell niche in the ovary undoubtedly plays an important role in endocrine function and follicle biology. Altogether, the studies reveal unexpected diversity and heterogeneity among ovarian somatic and germ cells, highlighting the prevailing knowledge gaps in basic ovarian biology. As the most common outcome for a follicle is atresia, it is possible that part of the cell diversity relates to the biology of follicles destined to degenerate. The absence of spatial coordinates in single-cell studies further complicates the interpretation of the roles and significance of the various reported cell clusters. Accomplishing a representative ovarian single-cell atlas will require merging these studies. However, direct comparisons are challenging due to nonuniform nomenclature, differing tissue sources, varying meta-data reporting, and lack of gold standards in technical approaches. Although these reports establish a single-cell draft of adult-fertile age human ovaries, more detailed metadata and better quality reporting will be essential for the development of a robust ovarian cell atlas in health and disease.
    Keywords:  RNA-sequencing; epigenetics; fertility; oocyte; ovarian follicle; ovary; proteomics; reproduction; single-cell
    DOI:  https://doi.org/10.1016/j.ajog.2024.05.046
  7. Dev Cell. 2025 Apr 21. pii: S1534-5807(25)00178-9. [Epub ahead of print]60(8): 1135-1137
    Nuage in color: Systematic protein tagging shows the compositional complexity of germ granules.
    Laura L Thomas, Devavrat M Bodas, Geraldine Seydoux.
      In this issue of Developmental Cell, Huang et al. generate a library of C. elegans strains to systematically characterize germ granule composition. This survey catalogs condensate proteins in an intact organism using endogenous tags and sets the stage for future studies of condensate composition and function.
    DOI:  https://doi.org/10.1016/j.devcel.2025.03.015
  8. Cell Death Differ. 2025 Apr 23.
    Combinatorial tagging generates a multi-purpose knock-in mouse model revealing phase separation-dependent germ granules in RNA homeostasis and germline development.
    Lan Meng, Caoling Xu, Yuzhu Cao, Limin Wu, Yuzhang Zhu, Jiaqi Zou, Islam Uddin, Iqra Zafar, Azhar Muhammad, Xuemei Xing, Ren-Tao Jin, Li He, Hongbin Liu, Wenqing Li, Jianqiang Bao.
      A large resource of epitope-tagged and Cre/CreERT2-expressing mouse models are available for studying germ granules and germline development. Germ granules are proteinaceous, membraneless organelles (MLO) involved in germ cell differentiation and maturation; however, their protein and RNA transcript constituents, as well as their functional mechanisms remain incompletely understood. Herein, we generated a versatile germline mouse model through combinatorially tagging DDX4 to enable simultaneous expression of three cistronic coding products (C-terminally tagged DDX4 - DDX45HA, EGFP, and CreERT2) under the control of the endogenous Ddx4 promoter. By leveraging the high-affinity HA tag, we optimized an efficient workflow to purify germ granules (Chromatoid body, CB) from spermatids, and characterized their protein and RNA transcript composition. Moreover, we explored and ascertained that DDX4-mediated, phase-separation dependent CB integrity is functionally important for recruiting distinctive long RNA transcripts and for the biogenesis of pachytene- and TE-derived piRNAs. Together, our study generated a versatile germline mouse model with a multiplicity of applications for germline study, and provided mechanistic insights into germline development as dictated by germ granules.
    DOI:  https://doi.org/10.1038/s41418-025-01495-7
  9. J Cell Biol. 2025 May 05. pii: e202412135. [Epub ahead of print]224(5):
    Telomeres, the nuclear lamina, and membrane remodeling: Orchestrating meiotic chromosome movements.
    Hiroki Shibuya.
      Telomeres, the DNA-protein complex located at the ends of linear eukaryotic chromosomes, not only safeguard genetic information from DNA erosion and aberrant activation of the DNA damage response pathways but also play a pivotal role in sexual reproduction. During meiotic prophase I, telomeres attach to the nuclear envelope and migrate along its surface, facilitating two-dimensional DNA homology searches that ensure precise pairing and recombination of the paternal and maternal chromosomes. Recent studies across diverse model systems have revealed intricate molecular mechanisms, including modifications to telomere- and nuclear envelope-binding proteins, the nuclear lamina, and even membrane composition. Emerging evidence reveals mutations in the genes encoding these meiotic telomere and nuclear envelope-associated proteins among infertile patients. This review highlights recent advances in the field of meiotic telomere research, particularly emphasizing mammalian model systems, contextualizes these findings through comparisons with other eukaryotes, and concludes by exploring potential future research directions in the field.
    DOI:  https://doi.org/10.1083/jcb.202412135
  10. Nat Commun. 2025 Apr 23. 16(1): 3805
    Three-dimensional genome structures of single mammalian sperm.
    Heming Xu, Yi Chi, Changjian Yin, Cheng Li, Yujie Chen, Zhiyuan Liu, Xiaowen Liu, Hao Xie, Zi-Jiang Chen, Han Zhao, Keliang Wu, Shigang Zhao, Dong Xing.
      The three-dimensional (3D) organization of chromosomes is crucial for packaging a large mammalian genome into a confined nucleus and ensuring proper nuclear functions in somatic cells. However, the packaging of the much more condensed sperm genome is challenging to study with traditional imaging or sequencing approaches. In this study, we develop an enhanced chromosome conformation capture assay, and resolve the 3D whole-genome structures of single mammalian sperm. The reconstructed genome structures accurately delineate the species-specific nuclear morphologies for both human and mouse sperm. We discover that sperm genomes are divided into chromosomal territories and A/B compartments, similarly to somatic cells. However, neither human nor mouse sperm chromosomes contain topologically associating domains or chromatin loops. These results suggest that the fine-scale chromosomal organization of mammalian sperm fundamentally differs from that of somatic cells. The discoveries and methods established in this work will be valuable for future studies of sperm related infertility.
    DOI:  https://doi.org/10.1038/s41467-025-59055-z
  11. Nat Commun. 2025 Apr 19. 16(1): 3722
    Vitellogenin receptor mediates heat adaptability of oocyte development in mud crabs and zebrafish.
    Long Zhang, Kun Wu, Haoyang Li, Minwen Zhan, Sheng Wang, Enhui Song, Qi Zhang, Jian He, Xinyi He, Menghuang Xu, Hengwei Deng, Yingchun Su, Ziwei Liu, Zhuyue Yan, Peipei Tan, Mengyun He, Shaoping Weng, Wei Ge, Jianguo He, Muhua Wang.
      Climate-driven warming affects the reproduction of oviparous ectotherms. However, whether oviparous ectotherms possess a protection mechanism against heat stress for oocyte development, which is essential for maintaining the continuity of animal populations, is largely unknown. Under high temperatures, female mud crabs (Scylla paramamosain) typically have well-formed ovaries, while a few crabs were found to experience oocyte development failure. To investigate the heat stress protection mechanism of oocyte development in mud crabs, we construct a chromosome-level genome of this species and identify an enhancer of the vitellogenin receptor (VtgR) that stimulates its expression under high temperatures. Lacking this enhancer due to an intronic deletion leads to low VtgR expression in abnormal crabs, resulting in abnormal vitellogenic oocyte formation in these individuals when exposed to high temperatures. Furthermore, we identify a similar heat stress protection mechanism in zebrafish. Disruption of Lrp13, a VtgR-like protein in zebrafish, results in impaired vitellogenin absorption and ovarian degeneration in zebrafish exposed to high temperatures. Our results reveal a VtgR-mediated mechanism that protects vitellogenic oocyte formation against heat stress in mud crabs and zebrafish, contributing to their heat adaptability during oocyte development.
    DOI:  https://doi.org/10.1038/s41467-025-59035-3
  12. Proc Natl Acad Sci U S A. 2025 Apr 29. 122(17): e2421185122
    A selfish supergene causes meiotic drive through both sexes in Drosophila.
    Graeme L Keais, Chadi M Saad-Roy, Emmanuel Gonzalez-Sqalli, Candice N Powell, Loren H Rieseberg, Ryan M R Gawryluk, P van den Driessche, Kevin H-C Wei, Benjamin Loppin, Steve J Perlman.
      Meiotic drivers are selfish genetic elements that bias their own transmission during meiosis or gamete formation. Due to the fundamental differences between male and female meiosis in animals and plants, meiotic drivers operate through distinct mechanisms in the two sexes: In females, they exploit the asymmetry of meiosis to ensure their inclusion in the egg, whereas in males, they eliminate competing gametes after symmetric meiosis. Meiotic drive is commonly reported in males, where it strongly influences the evolution of spermatogenesis, while the few known cases in females have highlighted its crucial role in centromere evolution. Despite a growing number of examples in a wide range of organisms, meiotic drive has so far only been observed in one sex or the other since its discovery nearly 100 y ago. Here, we show that a selfish X chromosome known to cause meiotic drive in male Drosophila testacea flies also causes meiotic drive in females. We find that this X chromosome has supergene architecture, harboring extensive structural rearrangements that suppress recombination between the two X chromosomes. This has contributed to a substantial expansion of its size compared to the wild-type chromosome, partly due to the accumulation of species-specific repetitive elements. Our findings suggest that female meiotic drive may play an important role in the evolutionary dynamics of polymorphic structural variants that suppress recombination, including inversions, translocations, and supergenes.
    Keywords:  meiotic drive; selfish genetic elements; sex chromosome; supergenes
    DOI:  https://doi.org/10.1073/pnas.2421185122
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