bims-cebooc Biomed News
on Cell biology of oocytes
Issue of 2026–08–30
thirteen papers selected by
Gabriele Zaffagnini, Universität zu Köln
  1. Mitochondrial DNA leakage in oocytes activates cGAS-STING signaling to drive ovarian aging.
  2. A transient RNP compartment boosts translation and growth of mammalian oocytes.
  3. Loss of Nemp1 disrupts female meiosis and activates a conserved ATM-CHK2 checkpoint.
  4. Elevated contractility drives implantation failure in mouse embryos from aged females.
  5. DDX3X-mediated rRNA condensate clearance during germinal vesicle breakdown facilitates chromosome segregation in oocytes.
  6. MEIOSIN retains a STRA8-independent activity that contributes to meiotic gene activation across vertebrates.
  7. The R-loop-SPT6-SETD2 axis safeguards H3K36me3 to prevent broad H3K4me3 invasion in mouse oocytes.
  8. The Fallopian tube: Biosensor and dynamic regulator of preimplantation development.
  9. ELAVL1 and ELAVL4 Are Required for Musashi-Dependent Translational Activation.
  10. Squash enables Spindle-E-dependent heterotypic piRNA amplification in the Drosophila ovary.
  11. PIWI proximity proteome reveals Set1-mediated piRNA biogenesis for transposon silencing at telomeres.
  12. A network of steroid receptor transcription factors regulates ovarian chromatin remodelling in the transition to ovulation.
  13. Ecologically relevant low oxygen levels reduce unfertilized oocyte output in Caenorhabditis elegans.
  1. Nat Aging. 2026 Aug 28.
    Mitochondrial DNA leakage in oocytes activates cGAS-STING signaling to drive ovarian aging.
    Min Lei, Zhenye Zhu, Huihui Xie, Chenlu Wei, Jiajia Zhu, Keer Wang, Kexin Zhang, Yongxing Yu, Linli Yang, Xiangyang Zhang, Ning Song, Diyi Xie, Ruizhi Guo, Yanqing Zhao, Aaron J W Hsueh, Yingpu Sun, Qingling Yang.
      Ovarian aging precedes decline in many organs, but its mechanisms remain unclear. Here we show that aging oocytes accumulate cytoplasmic mitochondrial DNA (mtDNA) through increased mtDNA leakage, activating the cyclic GMP-AMP synthase (cGAS) pathway to produce cGAMP and trigger stimulator of interferon genes (STING) signaling. Notably, oocyte-derived cGAMP can pass through gap junctions to surrounding granulosa cells (GCs), activating STING signaling in GCs as well. To model age-associated mitochondrial dysfunction, we generated oocyte-specific Tfam-knockout mice, which recapitulated mtDNA leakage, STING pathway activation in both oocytes and GCs, inflammation and accelerated ovarian dysfunction. We also used Opa1 knockdown and Pink1 deletion oocytes as complementary mitochondrial stress models and observed mtDNA leakage and cGAS-STING activation in both settings. Notably, oocyte-specific Cgas deletion in Tfam mutants or pharmacological STING inhibition with H-151 ameliorated ovarian dysfunction. These findings establish oocyte mtDNA leakage as a causal driver of ovarian aging and nominate cGAS-STING signaling as a therapeutic target.
    DOI:  https://doi.org/10.1038/s43587-026-01195-y
  2. Sci Adv. 2026 Aug 28. 12(35): eaej5359
    A transient RNP compartment boosts translation and growth of mammalian oocytes.
    Noemi Zollo, Gabriele Zaffagnini, Ali Haidar, Alexis Canette, Gaëlle Letort, Christelle Da Silva, Elsa Labrune, Nicolas Tessandier, Julien Dumont, Corinne Blugeon, Benoit Wattellier, Elvan Böke, Christopher Thomas, Maria Almonacid, Marie-Hélène Verlhac.
      Mammalian oocytes undergo an extended growth phase, during which transcription gradually declines. To sustain meiotic divisions and early embryonic development, growing oocytes must accumulate maternal stores and tightly regulate translation. Using immunofluorescence, mass spectrometry, electron microscopy, RNA sequencing, and live ex vivo ovarian tissue-slice imaging, we identified a transient ribonucleoprotein-organelle compartment in growing mouse oocytes, which we named the Zollo body. Although it resembles the Balbiani body observed in nongrowing oocytes of many vertebrate species, the Zollo body arises during growth and shows nascent translation and phospho-mTOR enrichment. Pharmacological dissolution of the Zollo body arrests follicle and oocyte growth in cultured ovarian tissue slices. Thus, the Zollo body is a transient, translation-associated compartment required for normal follicle and oocyte growth.
    DOI:  https://doi.org/10.1126/sciadv.aej5359
  3. Nat Commun. 2026 07 24. pii: 9100. [Epub ahead of print]17(1):
    Loss of Nemp1 disrupts female meiosis and activates a conserved ATM-CHK2 checkpoint.
    Bilal Ahmad Hakim, Yonit Tsatskis, Ling Zhang, Esther Choi, Ying Zhang, Didier Hodzic, Que Wu, MuYun Zhang, Maryam Pashaei, Kyungwon Ha, Jannette Rusch, Julie A Brill, Miguel Angel Brieño-Enríquez, Andrea Jurisicova, Helen McNeill.
      Female germ cells must preserve the integrity of their genome and generate genetic diversity via meiotic recombination. This challenging process is error prone. Highly conserved checkpoint pathways detect errors in recombination and DNA damage, inducing the death of defective oocytes. Nuclear Envelope Membrane Protein (NEMP) homologs are highly conserved proteins critical for fertility in flies, worms, fish and mice. They localize to the inner nuclear envelope where they provide mechanical support. However, why NEMP homologs are specifically required for fertility is still unclear. Using both Drosophila and mouse models, we establish that loss of NEMP homologs leads to activation of ATM and CHK2 kinases and inhibition of CHK2 or ATM rescues oocyte loss. In the absence of Nemp1, meiotic progression is delayed and DNA damage is increased at zygonema and pachynema stages. Loss of Nemp1 also leads to defects in chromosome synapsis persisting through pachynema. We conclude that NEMP1 is needed to protect genome integrity and is crucial for accurate chromosome pairing and synapsis, supporting oocyte developmental competence and survival.
    DOI:  https://doi.org/10.1038/s41467-026-75874-0
  4. Nat Cell Biol. 2026 Aug 25.
    Elevated contractility drives implantation failure in mouse embryos from aged females.
    Kate E Cavanaugh, M J Franco-Oñate, Nicole Horsley, Dilan Gokyer, Tomiris Atazhanova, Diana J Laird, Patrick W Oakes, Joan K Riley, Francesca E Duncan, MaryEllen Pavone, Matteo Molé, Ricard Alert, Orion D Weiner.
      Women in their mid-30s experience a marked decline in fertility. The origin of these fertility defects resides in the implantation capacity of the embryo itself, but the mechanistic basis of this impairment is not well understood. Here we identify a core mechanical defect in embryos from aged females that impairs their implantation competence. Using mouse models, we find that reproductive ageing drives excessive contractility in the trophectoderm, the outer epithelial lineage that enables implantation. This hypercontractility increases blastocyst tissue surface tension and viscosity, which hinders spreading during implantation. Elevated contractility is both necessary and sufficient for age-associated implantation failure. We identify non-invasive imaging signatures that infer embryo mechanics and predict implantation success for embryos of both young and aged females. Analyses of human embryos and in vitro fertilization clinical datasets reveal conserved age-associated mechanical alterations that correlate with implantation potential. Our work implicates embryo mechanics as a key regulator of reproductive longevity.
    DOI:  https://doi.org/10.1038/s41556-026-02052-1
  5. Biol Reprod. 2026 Aug 23. pii: ioag178. [Epub ahead of print]
    DDX3X-mediated rRNA condensate clearance during germinal vesicle breakdown facilitates chromosome segregation in oocytes.
    Xing An, Xiao-Peng Wang, Feng-Yun Xie, Yingyu Chen, Juan Chen, Xiang-Hong Ou, Jun-Yu Ma.
      During oocyte growth, rRNAs are transcribed in nucleolus and participate in ribosome formation, but dynamic changes of rRNAs during oocyte maturation haven't yet been studied. Using RNA-FISH, we found rRNAs in germinal vesicle breakdown (GVBD) stage oocytes and a small number of oocytes at the pro-metaphase of the first meiosis stage still associate with chromosomes, and can be labeled with 5-Ethynyl Uridine (5-EU). In oocytes, rDNA transcription factor UBTF are present within nucleoli at germinal vesicle (GV) stage or near chromosomes at GVBD stage. However, RNA polymerase I can only be found at GV but not GVBD oocytes. In contrast, RNA helicase DDX3X doesn't colocalize with UBTF in GV oocytes but does colocalize with UBTF in GVBD oocytes. During oocyte maturation, the proportion of oocyte with DDX3X focus gradually decrease after GVBD. At GVBD stage, both UBTF and DDX3X are associated with rRNA condensates. When treating oocytes with DDX3X inhibitor RK-33, the decrease of 5-EU signals in oocytes will be delayed. Both treatment of RK-33 or microinjection of mutated human DDX3X cRNAs significantly reduce polar body extrusion rate and increase rate of spindle abnormalities in oocytes. Based on these findings, we hypothesize that rRNA accumulated during GV stage may entangle condensed chromosomes during GVBD and impairs chromosome segregation, and RNA helicases such as DDX3X are recruited to rRNA condensate to facilitate its clearance, thereby promoting proper chromosome segregation in oocytes. These data reveal a novel mechanism regulating chromosome segregation in oocytes.
    Keywords:  DDX3X; GVBD; UBTF; chromosome segregation; oocyte; rRNA
    DOI:  https://doi.org/10.1093/biolre/ioag178
  6. Genes Dev. 2026 Aug 25.
    MEIOSIN retains a STRA8-independent activity that contributes to meiotic gene activation across vertebrates.
    Ryuki Shimada, Yukiko Imai, Kimi Araki, Toshihiro Kawasaki, Sakie Iisaka, Shingo Usuki, Kei-Ichiro Yasunaga, Sayoko Fujimura, Naoki Tani, Hitoshi Niwa, Shigehiro Kuraku, Noriyoshi Sakai, Kei-Ichiro Ishiguro.
      Meiotic entry in vertebrates has been viewed as a transcriptional switch driven by the MEIOSIN-STRA8 axis, but whether this represents the ancestral regulatory logic of meiosis has remained unclear. Here we combine comparative genomics with genetic and single-cell analyses in zebrafish and mice to show that MEIOSIN retains an intrinsic STRA8-independent activity. We identify Meiosin orthologs in zebrafish and hagfish, vertebrate lineages that lack Stra8, and show that these proteins retain the HMG domain but have lost the bHLH domain required for the canonical MEIOSIN-STRA8 interaction. In zebrafish, meiosin is transiently induced at meiotic entry in both sexes, yet its loss selectively disrupts the female germline, causing failure of oogenesis and female-to-male sex reversal. In mice, MEIOSIN lacking the bHLH domain still initiates key features of meiotic entry and partially activates meiotic target genes, although it fails to support full meiotic progression. Together, these findings support a model in which HMG-containing MEIOSIN provides a conserved core activity for meiotic gene activation, whereas STRA8 and the bHLH-mediated MEIOSIN-STRA8 interaction reinforce the efficiency and robustness of this program in lineages that retain the canonical module.
    Keywords:  evolution; germ cell; meiosis; meiotic entry; oocyte; scRNA-seq; spermatocyte; testis; transcription factor; zebrafish
    DOI:  https://doi.org/10.1101/gad.353802.126
  7. Cell Rep. 2026 Aug 24. pii: S2211-1247(26)00891-0. [Epub ahead of print]45(9): 117813
    The R-loop-SPT6-SETD2 axis safeguards H3K36me3 to prevent broad H3K4me3 invasion in mouse oocytes.
    Yingliang Sheng, Tianyan Guo, Ying Ma, Junzhi Liao, Rong Guo, Kui Ming Chan, Guangjin Pan, Cizhong Jiang, Hongjie Yao.
      The orderly establishment of chromatin modifications is essential for oocyte maturation. However, how R-loops contribute to the crosstalk between histone modifications during oocyte development remains unexplored. Here, we demonstrate that R-loop resolution by RNASEH1 significantly compromises the developmental potential of oocytes. R-loops facilitate H3K36me3 deposition by stabilizing histone H3K36 methyltransferase SETD2 via histone chaperone SPT6 in germinal vesicle (GV) oocytes. Loss of R-loops reduces H3K36me3 levels within oocyte-specific gene bodies, triggering broad H3K4me3 invasion into H3K36me3-marked regions and repression of gene expression. dCas9-mediated site-specific restoration of SETD2 recruitment at R-loop-dependent loci effectively rescues local gene expression. Furthermore, Supt6 overexpression substantially rescues the imbalanced deposition between H3K36me3 and H3K4me3 caused by R-loop loss, corrects dysregulated gene expression, and alleviates the meiotic arrest phenotype. Collectively, our findings establish that R-loops act as critical regulators in balancing H3K36me3 and broad H3K4me3 in the maternal genome, thereby safeguarding proper oocyte development.
    Keywords:  CP: molecular biology; H3K36me3; H3K4me3; Meiotic arrest; Oocyte development; R-loop; SETD2; SPT6
    DOI:  https://doi.org/10.1016/j.celrep.2026.117813
  8. PNAS Nexus. 2026 Aug;5(8): pgag276
    The Fallopian tube: Biosensor and dynamic regulator of preimplantation development.
    Kalli K Stephens, Jiude Mao, Wipawee Winuthayanon.
      The Fallopian tube (also called the oviduct) provides the physiological site for fertilization and early embryonic development in mammals, yet its role in shaping preimplantation developmental competence remains incompletely understood. Although assisted reproductive technologies (ARTs) have enabled millions of successful pregnancies, most ART procedures bypass the oviduct, eliminating early embryo-maternal interactions that occur in vivo. Evidence across mammalian species demonstrates that the oviduct is not a passive conduit, but a dynamic tissue that regulates embryo transport, modulates immune and metabolic responses, and secretes stage-specific factors that influence embryonic development. Disruption of oviductal signaling impairs preimplantation development and leads to early pregnancy loss, highlighting the importance of a functional oviductal environment. Moreover, embryos actively send signals to the oviduct, eliciting stage-specific transcriptional and proteomic responses, indicating reciprocal communication during early pregnancy. Data suggest that embryos generated by different ART approaches (such as somatic cell nuclear transfer or artificial insemination) exhibit distinct molecular and metabolic profiles, raising the possibility that embryo source and quality may uniquely shape uterine epithelial responses following transfer. In this review, we provide evidence supporting the oviduct as an active regulator of preimplantation embryonic development, discuss the consequences of bypassing the oviduct in ART, and highlight current experimental models and knowledge gaps. Defining how the oviduct functions as a biosensor of embryo quality will be critical for understanding early pregnancy loss and refinements for ARTs.
    Keywords:  Fallopian tube; assisted reproductive technologies; embryo quality; embryo-maternal communication; oviduct
    DOI:  https://doi.org/10.1093/pnasnexus/pgag276
  9. Biomolecules. 2026 Jul 31. pii: 1119. [Epub ahead of print]16(8):
    ELAVL1 and ELAVL4 Are Required for Musashi-Dependent Translational Activation.
    Katherine Bronson, Milla M Reddick, Kenzie B Macnicol, Cole Bolen, Linda Hardy, Alex Lagasse, Angela K Odle, Gwen V Childs, Melanie C MacNicol, Angus M MacNicol.
      The RNA-binding proteins Musashi1 and Musashi2 (MSI1 and MSI2) regulate stem cell function and tissue plasticity by modulating mRNA translation. While typically known as translational repressors, the MSI1 and MSI2 proteins can also act as context-dependent activators of mRNA translation, although the mechanism of MSI-mediated translational activation is unknown. Here, we identify Embryonic Lethal Abnormal Vision-like (ELAVL) proteins as essential co-regulators of MSI1-dependent translational activation. In Xenopus laevis oocytes, antisense oligonucleotide knockdown of Elavl4 inhibited progesterone-stimulated maturation and blocked polyadenylation and translation of key MSI target mRNAs, including the Mos and Cyclin B5 mRNAs. Exogenous expression of ELAVL4 rescued these defects, confirming its necessity for maturation and cell cycle progression. Mechanistically, we determined that the ELAVL4 C-terminal domain interacts with the N-terminal RNA recognition motifs of MSI1 in an RNA-independent manner. Mass spectrometry and functional assays revealed this interaction is evolutionarily conserved: mouse ELAVL1 interacts with MSI1 in the pituitary, and human ELAVL1 rescues Elavl4-depleted Xenopus oocytes. Furthermore, knockdown of Elavl1 in a mammalian cell line abrogated MSI-dependent translational activation of a pituitary Prop1 3' UTR mRNA reporter. Our results establish a conserved mechanism where ELAVL family members interact with MSI to promote MSI-dependent mRNA translational activation.
    Keywords:  ELAVL; MSI; mRNA translation; oocyte; pituitary
    DOI:  https://doi.org/10.3390/biom16081119
  10. iScience. 2026 Aug 21. 29(8): 116920
    Squash enables Spindle-E-dependent heterotypic piRNA amplification in the Drosophila ovary.
    Xin Xu, Taichiro Iki, Shinichi Kawaguchi, Toshie Kai.
      The PIWI-interacting RNA (piRNA) pathway represses mobile transposable elements (TEs) to protect genome integrity in animal gonads. In Drosophila ovaries, piRNAs are generated in the nuage, a membrane-less organelle enriched with piRNA factors. Squash (Squ) is a key component for piRNA-mediated TE silencing, but its molecular function remains unclear. Here, we show that loss of Squ impairs piRNA biogenesis, causing abnormal accumulation of precursor transcripts and destabilization of Ago3. Reduction of Ago3 enhances Aub-Aub homotypic ping-pong instead of Aub-Ago3 heterotypic piRNA amplification. Furthermore, we demonstrate that Squ acts as a cofactor of the RNA helicase spindle-E (Spn-E), which is crucial for piRNA biogenesis. Disrupting the Squ-Spn-E interaction leads to TE de-repression and defective precursor processing, indicating that Squ cooperates with Spn-E to ensure proper piRNA biogenesis. Together, these findings identify Squ as a critical factor for Spn-E-dependent heterotypic piRNA amplification in the Drosophila ovary.
    Keywords:  Drosophila; Spindle-E; Squash; nuage; piRNA; transposon
    DOI:  https://doi.org/10.1016/j.isci.2026.116920
  11. EMBO Rep. 2026 Aug 26.
    PIWI proximity proteome reveals Set1-mediated piRNA biogenesis for transposon silencing at telomeres.
    Wakana Isshiki, Hiroko Kozuka-Hata, Masaaki Oyama, Toshie Kai, Taichiro Iki.
      Silencing complexes formed by PIWI-clade Argonaute (Ago) proteins and PIWI-interacting RNAs (piRNAs) are essential guardians of genome integrity, restricting the activities of transposable elements (TEs) in the animal germline. However, our understanding of PIWI-piRNA-directed TE silencing remains incomplete. Here, we systemically characterize the proximity proteome of the PIWI members Piwi, Aubergine (Aub), and Ago3 in the germline of Drosophila ovaries. Functional screening identifies previously uncharacterized factors involved in TE silencing, including the H3K4me3 writer and transcriptional coactivator Set1. Transcriptome analysis reveals that Set1 acts as an indispensable repressor of TEs, particularly of those at telomeres. Set1 is required for the production of antisense, TE-targeting piRNAs. Genome-wide chromatin profiling by CUT&Tag demonstrates that Set1 preferentially associates with TE sequences, including their 3'UTRs, and is localized at subtelomeric piRNA-producing loci. It also controls the accumulation of Rhino, a key activator of piRNA precursor transcription, at these sites. Notably, the catalytic activity of Set1 is dispensable. Our findings uncover a noncanonical function of Set1 in Piwi-mediated TE silencing in germline nuclei.
    DOI:  https://doi.org/10.1038/s44319-026-00901-6
  12. Genome Res. 2026 Aug 25. pii: gr.282066.126. [Epub ahead of print]
    A network of steroid receptor transcription factors regulates ovarian chromatin remodelling in the transition to ovulation.
    Doan Thao Dinh, Rebecca L Robker, Darryl L Russell.
      Steroid receptors are transcription factors activated by progesterone (PGR), androgen (AR) and glucocorticoid (GR) that bind the same canonical DNA sequence to modulate genome function in response to steroid hormones. However, the mechanisms defining unique physiological roles of these conserved receptors within the same tissue context, including the ovary, remains elusive. We describe the dynamic association between each steroid receptor cistrome in the mouse ovary responding to the hormonal switch from follicle development to ovulation, and generate chromatin conformation maps to define steroid receptor roles in promoter-enhancer interactions and gene transcription. Ovulatory hormones trigger PGR and GR binding to novel chromatin sites, promoting transcriptional activation of genes that are required for ovulation, whereas AR-chromatin interactions and AR-associated genes are repressed. Integration of genomic and transcriptomic data illustrates two parallel modes of PGR-mediated gene activation. Unique cooperation between PGR and GR enables their recruitment to previously inaccessible promoters, increasing histone acetylation, chromatin accessibility and transcription activation, with PGR being the indispensable component of this transcriptional complex. Alternatively, PGR tethered to enhancers interacts with preaccessible, AR/GR-bound promoters induces gene activation. Our findings illustrate the multifaceted steroid receptor interactions that translate progressive change in steroid environments to collectively reprogram granulosa cell genome function to switch from follicle development to ovulation.
    DOI:  https://doi.org/10.1101/gr.282066.126
  13. MicroPubl Biol. 2026 ;2026
    Ecologically relevant low oxygen levels reduce unfertilized oocyte output in Caenorhabditis elegans.
    Emma R Haxen, Mazharul Islam, Alexandra Grabowski, Sofie Mohlin, Nicole R Posth, Sandeep Gopal, Emma U Hammarlund.
      Caenorhabditis elegans naturally inhabits low-oxygen environments but is typically studied at 21% oxygen. We cultured adult C. elegans at 2.5%, 5%, and 21% oxygen during the fertile period, quantifying daily output of hatched larvae, unfertilized oocytes, and abnormal progeny (unhatched embryos, dead or deformed larvae). While we found no evidence for increased fertility at low oxygen levels compared to 21%, we observed a trend towards fewer unfertilized oocytes after peak fertility at 5% oxygen and significantly fewer at 2.5%. Our results indicate that reproductive output differs between laboratory conditions (high oxygen) and moderately low oxygen levels (closer to natural environments).
    DOI:  https://doi.org/10.17912/micropub.biology.002266
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