bims-cebooc Biomed News
on Cell biology of oocytes
Issue of 2025–12–07
thirteen papers selected by
Gabriele Zaffagnini, Universität zu Köln
  1. Fertilization triggers early proteomic symmetry breaking in mammalian embryos.
  2. Intercellular diffusion of cyclic nucleotides followed by gap junction closure restarts meiosis in mouse preovulatory follicles.
  3. Major waves of H2A.Z incorporation during mouse oogenesis and preimplantation embryo development.
  4. MYCBP interacts with Sakura and Otu and is essential for germline stem cell renewal and differentiation and oogenesis.
  5. Methods for Analyzing Lipid Droplets in Mammalian Oocytes and Fertilized Embryos.
  6. Trans-generational maintenance of mitochondrial DNA integrity in oocytes during early folliculogenesis.
  7. Morphogenesis: Pressure from within shapes the egg.
  8. Systematic analysis of noncanonical ribosomal protein paralogs does not provide evidence for specialized functions in Drosophila.
  9. Doppler Ultrasonography for Live Imaging and Quantification of Ovarian Vascular Function in Mice.
  10. The Role of STING-Mediated Activation of the Integrated Stress Response in Inflammation-Induced Depletion of Ovarian Reserve.
  11. Microbiota safeguards ovarian reserve and extend reproductive lifespan.
  12. AMPK modulates a DEAH box RNA-helicase to attenuate TOR signaling and establish developmental quiescence in Caenorhabditis elegans.
  13. Polar cell membrane nanotubes containing microtubules and acidic vesicles render Drosophila eggs fertile.
  1. Cell. 2025 Dec 03. pii: S0092-8674(25)01255-3. [Epub ahead of print]
    Fertilization triggers early proteomic symmetry breaking in mammalian embryos.
    Lisa K Iwamoto-Stohl, Aleksandra A Petelski, Baiyi Quan, Maciej Meglicki, Audrey Fu, Shoma Nakagawa, Breanna McMahon, Ting-Yu Wang, Saad Khan, Harrison Specht, Gray Huffman, Jason Derks, Sergi Junyent, Bailey A T Weatherbee, Antonia Weberling, Carlos W Gantner, Rachel S Mandelbaum, Richard J Paulson, Lisa Lam, Tsui-Fen Chou, Nikolai Slavov, Magdalena Zernicka-Goetz.
      While non-mammalian embryos often rely on spatial pre-patterning, mammalian development has long been thought to begin with equivalent blastomeres. However, emerging evidence challenges this. Here, using multiplexed and label-free single-cell proteomics, we identify over 300 asymmetrically abundant proteins-many involved in protein degradation and transport-dividing mouse 2-cell-stage blastomeres into two distinct clusters, which we term alpha and beta. These proteomic asymmetries are detectable as early as the zygote stage, intensify by the 4-cell stage, and correlate with the sperm entry site, implicating fertilization as a symmetry-breaking event. Splitting 2-cell-stage embryos into halves reveals that beta blastomeres possess greater developmental potential than alpha blastomeres. Similar clustering and protein enrichment patterns found in human 2-cell embryos suggest this early asymmetry might be conserved. These findings uncover a previously unrecognized proteomic pre-patterning triggered by fertilization in mammalian embryos, with important implications for understanding totipotency and early lineage bias.
    Keywords:  2-cell blastomere asymmetries; developmental biology; embryonic patterning; epiblast; human development; lineage specification; mammalian embryonic development; pre-implantation development; single-cell proteomics by mass spectrometry; totipotency
    DOI:  https://doi.org/10.1016/j.cell.2025.11.006
  2. Proc Natl Acad Sci U S A. 2025 Dec 09. 122(49): e2524136122
    Intercellular diffusion of cyclic nucleotides followed by gap junction closure restarts meiosis in mouse preovulatory follicles.
    Iris F Nakashima, Haining Zhong, Viacheslav O Nikolaev, Corie M Owen, Siu-Pok Yee, Laurinda A Jaffe, Jeremy R Egbert.
      Signaling by luteinizing hormone (LH) in the outer granulosa cells of mammalian ovarian follicles causes meiosis to resume in the oocyte, located ~10 cell layers away, preparing the oocyte for ovulation and fertilization. This long-distance communication is accomplished by cAMP and cGMP diffusion through gap junctions, but knowledge of cAMP dynamics in the oocyte is based on static measurements, and information about cAMP changes in the granulosa cells has not been integrated with information about cAMP changes in the oocyte. By simultaneous multihour imaging of both compartments of live ovarian follicles, using mice expressing an improved cAMP sensor, we elucidate how the meiosis-activating signal is transmitted. In response to LH, cAMP generated in the granulosa cells diffuses within ~10 min to the oocyte. cAMP in the granulosa cells then remains high for at least 5 h, but over a 3-h period, cAMP in the oocyte decreases to a new plateau level below the original baseline. We show that the cAMP decrease in the oocyte depends not only on the established mechanism of LH lowering cGMP in the oocyte, which relieves inhibition of the PDE3A phosphodiesterase in the oocyte, but also on the subsequent LH-induced closure of gap junctions between the granulosa cells. This closure prevents cAMP from diffusing into the oocyte from the granulosa cells, a concept that has been proposed but not previously tested. We conclude that LH coordinates changes in both cGMP and gap junctions to lower cAMP in the oocyte, reinitiating meiotic progression.
    Keywords:  cyclic nucleotides; gap junctions; luteinizing hormone; oocyte meiosis; ovarian follicle
    DOI:  https://doi.org/10.1073/pnas.2524136122
  3. Nat Commun. 2025 Dec 02.
    Major waves of H2A.Z incorporation during mouse oogenesis and preimplantation embryo development.
    Madeleine Fosslie, Erkut Ilaslan, Trine Skuland, Michel Choudalakis, Mirra Søegaard, Jason Alexander Halliwell, Shaista Khan, Marie Indahl, Maria Vera-Rodriguez, Adeel Manaf, Annika Vera Geijer-Simpson, Rajikala Suganthan, Ingunn Jermstad, Knut Tomas Dalen, Ragnhild Eskeland, Elisabeth Kommisrud, Arne Klungland, Magnar Bjørås, Peter Fedorcsak, Gareth D Greggains, Mika Zagrobelny, John Arne Dahl, Mads Lerdrup.
      Epigenomes of mammalian oocytes and embryos undergo major transitions essential for successful development. Here, we provide genome-wide maps of histone variant H2A.Z during twelve stages of mouse oogenesis and preimplantation embryo development and relate it to histone marks and genomic features. This revealed that major waves of H2A.Z incorporation occur early in growing oocytes, forming distinct patterns of maternal, embryonic, and persistent H2A.Z enrichment. Late maternal enrichment is inherited by the zygote and precedes reduced formation of lamina associated domains and early replication in the maternal genome of 2-cell embryos. Persistent H2A.Z enrichment is strongly associated with CpG islands and H3K4me3 near transcription start sites of active genes, but thousands of maternal and embryonic H2A.Z incorporation sites exist elsewhere, frequently at transposable elements. The persisting H2A.Z enrichments across related developmental stages enable preservation of epigenetic information despite major concurrent changes in H3K4me3, H3K27me3, and DNA methylation. Altogether, this advances our understanding of how histone variants contribute to epigenetic reprogramming during mammalian oogenesis and early development.
    DOI:  https://doi.org/10.1038/s41467-025-66919-x
  4. PLoS Genet. 2025 Dec;21(12): e1011792
    MYCBP interacts with Sakura and Otu and is essential for germline stem cell renewal and differentiation and oogenesis.
    Azali Azlan, Ryuya Fukunaga.
      The self-renewal and differentiation of germline stem cells (GSCs) are tightly regulated during oogenesis. The Drosophila female germline provides a powerful model to study these regulatory mechanisms. We previously identified Sakura (also known as Bourbon/CG14545) as a crucial factor for maintenance and differentiation of GSCs and oogenesis, and demonstrated that Sakura binds to Ovarian Tumor (Otu), another essential regulator of these processes. Here, we identify MYCBP (c-Myc binding protein) as an additional essential component of this regulatory network. We show that MYCBP physically associates with itself, Sakura, and Otu, forming binary and ternary complexes including a MYCBP•Sakura•Otu complex. MYCBP is highly expressed in the ovary, and mycbp null mutant females exhibit rudimentary ovaries with germline-less and tumorous ovarioles, fail to produce eggs, and are completely sterile. Germline-specific depletion of mycbp disrupts Dpp/BMP signaling, causing aberrant expression of bag-of-marbles (bam) and leading to defective differentiation and GSC loss. In addition, mycbp is required for female-specific splicing of sex-lethal (sxl), a master regulator of sex identity determination. These phenotypes closely resemble those observed in sakura and otu mutants. Together, our findings reveal that MYCBP functions in concert with Sakura and Otu to coordinate self-renewal and differentiation of GSCs and oogenesis in Drosophila.
    DOI:  https://doi.org/10.1371/journal.pgen.1011792
  5. Reprod Med Biol. 2025 Jan-Dec;24(1):24(1): e70002
    Methods for Analyzing Lipid Droplets in Mammalian Oocytes and Fertilized Embryos.
    Megumi Ibayashi, Satoshi Tsukamoto.
       Background: Lipid droplets (LDs) are organelles consisting of a central core of neutral lipids covered by a single layer of phospholipids and are found in most eukaryotic cells. It has long been known that mammalian oocytes accumulate different amounts of LDs between animals; however, it is largely unknown why LD content varies from animal to animal and its physiological role remains unclear. Reflecting the growing interest in LDs in mammalian oocyte and early embryos, several comprehensive reviews have appeared in the last few years, but none have reviewed methods for visualizing and analyzing LDs stored in oocytes or fertilized eggs.
    Methods: We outline experimental methods for visualizing LDs in mammalian oocytes and early embryos. We also describe a method for LD degradation by fertilization-induced autophagy and a centrifugation-based method for the removal of LDs from ovulated metaphase II (MII) oocytes in mice.
    Main Findings: This review outlines the advantages and disadvantages of some of the typical methods for observing and analyzing LDs in oocytes and fertilized embryos.
    Conclusion: Our review provides useful information not only to basic researchers interested in LDs in mammalian oocytes and fertilized embryos, including humans, but also to embryologists and medical doctors.
    Keywords:  embryo; lipid droplet; methods; mouse; oocyte
    DOI:  https://doi.org/10.1002/rmb2.70002
  6. PLoS Genet. 2025 Dec 03. 21(12): e1011562
    Trans-generational maintenance of mitochondrial DNA integrity in oocytes during early folliculogenesis.
    Qin Xie, Haibo Wu, Jiaxin Qiu, Junbo Liu, Xueyi Jiang, Huihui Wu, Qifeng Lyu, Hui Long, Wenzhi Li, Shuo Zhang, Yuxiao Zhou, Yining Gao, Aaron J W Hsueh, Yanping Kuang, Lun Suo.
      Mutations in mitochondrial DNA (mtDNA) can lead to mitochondrial and cellular dysfunction. However, recent studies suggest that purifying selection acts against mutant mtDNAs during transgenerational transmission. We investigated the mtDNA dynamics during ovarian follicle development. Using base-editing, we generated mice harboring a 3177 G > A mutation corresponding to the human Leber hereditary optic neuropathy (LHON)-related mtDNA mutation and confirmed a transgenerational reduction of the mutant mtDNA. Utilizing a mouse follicle culture system in which pathogenic mtDNA mutations were introduced in vitro, followed by mtDNA sequencing and digital PCR, we found that the germline heteroplasmy shift during early folliculogenesis was driven by a decrease in mutant mtDNA along with compensatory replication of wild-type mtDNA. In contrast, synonymous mtDNA mutations did not affect mtDNA dynamics. These findings demonstrate that mice can eliminate certain pathogenic mtDNA mutations in the germline during early folliculogenesis, thus advancing our understanding of mtDNA purifying selection during oogenesis. Furthermore, our use of mtDNA editing in in vitro-cultured follicles provides a novel approach to create and monitor mitochondrial DNA mutations.
    DOI:  https://doi.org/10.1371/journal.pgen.1011562
  7. Curr Biol. 2025 Dec 01. pii: S0960-9822(25)01383-1. [Epub ahead of print]35(23): R1146-R1149
    Morphogenesis: Pressure from within shapes the egg.
    Soline Chanet, Jean-René Huynh.
      A new study explores the role of mechanical pressure in regulating morphogenesis during Drosophila oogenesis. Actomyosin contractility is mechanically patterned in space and time in somatic cells by the growth of the underlying germline cells via a process involving the activation of the calcium channel TRPM.
    DOI:  https://doi.org/10.1016/j.cub.2025.10.040
  8. Proc Natl Acad Sci U S A. 2025 Dec 09. 122(49): e2506642122
    Systematic analysis of noncanonical ribosomal protein paralogs does not provide evidence for specialized functions in Drosophila.
    Katarina Z A Grobicki, Daniel Gebert, Carol Sun, Felipe Karam Teixeira.
      Ribosomes catalyze all protein synthesis, and mutations altering their levels and function underlie many developmental diseases and cancer. Historically considered to be invariant machines, ribosomes differ in composition between tissues and developmental stages, incorporating a diversity of ribosomal proteins (RPs) encoded by duplicated paralogous genes. Here, we use Drosophila to systematically investigate the origins and functions of noncanonical RP paralogs. We show that new paralogs mainly originated through retroposition and that only a few new copies retain coding capacity over time. Although transcriptionally active noncanonical RP paralogs often present tissue-specific expression, we show that the majority of those are not required for either viability or fertility in Drosophila melanogaster. The only exception, RpS5b, which is required for oogenesis, is functionally interchangeable with its canonical paralog, indicating that the RpS5b-/- phenotype results from insufficient ribosomes rather than the absence of an RpS5b-specific, functionally specialized ribosome. Altogether, our results provide evidence that instead of new functions, RP gene duplications provide a means to regulate ribosome levels during development.
    Keywords:  germline; ribosome heterogeneity; translational control
    DOI:  https://doi.org/10.1073/pnas.2506642122
  9. J Vis Exp. 2025 Nov 14.
    Doppler Ultrasonography for Live Imaging and Quantification of Ovarian Vascular Function in Mice.
    Justine M Galliou, Samantha R Greenspun, Jackson Sapuleni, Rebecca M Williams, Yi Athena Ren.
      To effectively assess ovarian vascular function and understand its role in ovarian physiology and pathology, non-invasive in vivo approaches are essential for capturing real-time changes without disrupting normal blood flow. Doppler ultrasonography is a well-established, non-invasive tool for assessing ovarian blood flow in larger species, but its application has been limited in mice, which are one of the most widely used animal models for research in ovarian biology, such as ovulation. Ovulation is a tightly regulated process that depends on coordinated follicular maturation stimulated by follicle-stimulating hormone, followed by a preovulatory luteinizing hormone (LH) surge that leads to rupture of the follicle wall and release of oocytes for fertilization. The LH surge also triggers a series of structural and functional changes in the ovarian vasculature (vascular remodeling), such as angiogenesis and constriction of capillaries at the follicular rupture site shortly before ovulation. In addition, a rapid increase in ovarian blood flow following the LH surge has been reported in multiple species but not in mice. This protocol utilizes Doppler ultrasonography to visualize the murine ovarian vasculature and quantify hemodynamic parameters. The protocol presented here reports detailed methods for hormone priming, anesthesia, positioning of the mouse, identification of the ovary and its vasculature using power and color Doppler, and measurement of blood flow velocity and resistance parameters. This method enables real-time, longitudinal assessment of ovarian vascular function in live mice, providing a powerful tool for studying ovarian vascular function in both physiological and pathological contexts.
    DOI:  https://doi.org/10.3791/69169
  10. FASEB J. 2025 Dec 15. 39(23): e71286
    The Role of STING-Mediated Activation of the Integrated Stress Response in Inflammation-Induced Depletion of Ovarian Reserve.
    Qiumin Wang, You Wu, Xiaotong Dong, Yuxiu Wu, Yu Dai, Yongzhi Cao, Yanbo Du, Hong Lv, Keke Wei, Lianbao Cao, Lei Yan.
      Inflammatory responses within the ovarian microenvironment are increasingly recognized as significant disruptors of ovarian function, yet their specific effects on early follicular development, particularly the activation of primordial follicles, remain poorly understood. In this study, we employ a mouse model of transient lipopolysaccharide (LPS)-induced inflammation to mimic the inflammatory conditions associated with chronic pelvic inflammatory disease (PID) and systemic infections. We demonstrate that LPS stimulation triggers the premature activation of primordial follicles, leading to a depletion of the ovarian reserve. This finding underscores the detrimental impact of inflammation on ovarian health. However, we also identify a protective mechanism mediated by the cGAS-STING pathway, a central regulator of innate immunity and cellular stress responses. Activation of the cGAS-STING pathway effectively inhibits LPS-induced primordial follicle activation, thereby preserving ovarian function. Further mechanistic investigations reveal that the Integrated Stress Response (ISR), a downstream effector of STING signaling, plays a critical role in this protective process. The ISR, orchestrated by kinases such as PERK, modulates cellular homeostasis under stress conditions by phosphorylating eukaryotic initiation factor 2α (eIF2α). Our data show that STING activation induces ISR signaling, which in turn suppresses the overactivation of primordial follicles. To explore the therapeutic potential of this pathway, we utilized STING and ISR agonists, which successfully mitigated LPS-induced primordial follicle activation and preserved ovarian reserve in our experimental model. These findings highlight the dual role of inflammation in ovarian biology: while acute inflammatory stimuli can disrupt follicular quiescence, the cGAS-STING-ISR axis serves as a critical regulatory network to counteract these adverse effects. Our study not only elucidates the molecular mechanisms underlying inflammation-induced ovarian dysfunction but also identifies STING and ISR as promising therapeutic targets for preserving ovarian reserve in women exposed to chronic inflammatory conditions. These insights have significant clinical implications, offering potential strategies to protect ovarian function in patients with inflammatory diseases or those undergoing treatments that compromise ovarian health.
    DOI:  https://doi.org/10.1096/fj.202502370RR
  11. Nat Aging. 2025 Dec 05.
    Microbiota safeguards ovarian reserve and extend reproductive lifespan.
    Yahyah Aman.
      
    DOI:  https://doi.org/10.1038/s43587-025-01042-6
  12. PLoS Biol. 2025 Dec 01. 23(12): e3003144
    AMPK modulates a DEAH box RNA-helicase to attenuate TOR signaling and establish developmental quiescence in Caenorhabditis elegans.
    Sabih Rashid, Richard Roy.
      Developmental plasticity allows organisms to adapt to environmental stress and improve reproductive fitness. Caenorhabditis elegans adapts to starvation and other stressors by transiting through an alternate developmental stage called dauer, which allows them to remain quiescent for several months, and yet fully retain reproductive fitness when they resume development. The AMP-activated protein kinase (AMPK) is essential for animals to passage through the dauer stage without reproductive consequence. The loss of AMPK leads to germline hyperplasia, dramatically reduced post-dauer fertility, and shortened dauer survival. We identified a putative RNA-binding helicase (HZL-1) that is targeted by AMPK. Disabling HZL-1 function rescues many dauer and post-dauer reproductive defects typical of the AMPK mutants. HZL-1 shares significant similarity with the conserved HELZ family of RNA helicases, possessing characteristic DEAH helicase motifs, a predicted ATP binding motif, and intrinsically disordered regions that are crucial for its localization and function. Curiously, HZL-1 is expressed and exerts its function in the intestine, yet its elimination suppresses the aberrant germ cell proliferation while restoring germline quiescence and subsequent post-dauer fertility in AMPK mutants. CLIP-seq data revealed that HZL-1 binds several mRNAs during the dauer stage, and thus when it is active in AMPK mutants, its regulation of these RNAs contributes to germline hyperplasia in the dauer germ line. The most enriched RNA bound and inhibited by HZL-1, argk-1, promotes fertility by suppressing TOR activity in the germ line of dauer larvae, thereby preserving germline quiescence. These findings underscore the intricate role of RNAs and RNA-binding helicases in the complex interplay of genetic signals that animals have acquired to ensure their effective transit through periods of environmental challenge.
    DOI:  https://doi.org/10.1371/journal.pbio.3003144
  13. PLoS Biol. 2025 Dec 02. 23(12): e3003533
    Polar cell membrane nanotubes containing microtubules and acidic vesicles render Drosophila eggs fertile.
    Sayan Acharjee, Banhisikha Saha, Neha Kumari, Jayeeta Nandi, Sudipta Adhya, Partha Protim Karmakar, Mohit Prasad.
      Membrane nanotubes serve as critical cytoskeletal structures that facilitate intercellular communication and signal transmission across distances in both plants and animals. Here, we report the role of microtubule (MT) nanotubes in rendering the Drosophila micropyle functional, a structure essential for sperm entry during fertilization. Our study highlights that MT-nanotubes emanate from the apical end of the specialized epithelial cells called the polar cells in late oogenesis, forming a narrow channel through the eggshell. Utilizing a combination of fly genetics, live cell imaging, and tissue immunochemistry, our research elucidates the structural and functional characteristics of the polar cell nanotube. We show that tubulin is vital for the formation of these nanotubes, which are enriched in the lateral membrane marker, Fasciclin III. Moreover, the overall polarity of the migrating cell cluster is critical for the successful development of the micropyle. Notably, both lysosomal function and lysosomal trafficking within the polar cells are essential for the opening of the vitelline layer, further facilitating the micropyle's role in fertilization.
    DOI:  https://doi.org/10.1371/journal.pbio.3003533
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