bims-cebooc 2026-01-18 papers

bims-cebooc

Biomed News

on Cell biology of oocytes

Issue of 2026–01–18
fourteen papers selected by
Gabriele Zaffagnini, Universität zu Köln

Programmed mitophagy at the oocyte-to-zygote transition promotes lineage endurance.
The intrinsic impact of mechanical stress on the maintenance of oocyte dormancy.
MEIOC prevents continued mitotic cycling and promotes meiotic entry during mouse oogenesis.
hnRNPU Safeguards Oocyte Development and Female Fertility via Regulation of Alternative Splicing.
SYMPK interacts with KIF20A and NUMA1 to coordinate spindle organization and safeguard oocyte meiotic maturation.
Balanced DNA-to-cytoplasm ratio at the 2-cell stage is critical for mouse preimplantation development.
Differential contributions of β-tubulin isotypes to acentrosomal oocyte meiosis in C. elegans.
Maternal TDP43 orchestrates nuclear speckle assembly and zygotic splicing activation during oocyte-to-embryo transition in mice.
Decreased PTGES2 Farnesylation in Granulosa Cells Compromises PGE2-Dependent Cumulus Expansion and Oocyte Maturation During Ovarian Aging.
Active maintenance of meiosis-specific chromosome structures in C. elegans by the deubiquitinase DUO-1.
SLBP-independent control of maternal histone mRNA.
H3K27me3-dependent imprinting and transcriptional regulation in early mouse embryos requires EZHIP-mediated restriction of PRC2 activity.
Tracing refractile body biogenesis in human oocytes: the role of lysosomes and mitochondria.
LOTUS-domain proteins activate Vasa to drive germ granule assembly.

Nat Cell Biol. 2026 Jan 12.

Programmed mitophagy at the oocyte-to-zygote transition promotes lineage endurance.

Siddharthan B Thendral, Sasha Bacot, Ian T Ryde, Katherine S Morton, Qiuyi Chi, Isabel W Kenny-Ganzert, Joel N Meyer, David R Sherwood.

The quality of mitochondria inherited from the oocyte determines embryonic viability, lifelong metabolic health of the progeny and lineage endurance. High levels of endogenous reactive oxygen species and exogenous toxicants pose threats to mitochondrial DNA (mtDNA) in fully developed oocytes. Deleterious mtDNA is commonly detected in mature oocytes, but is absent in embryos, suggesting the existence of a cryptic purifying selection mechanism. Here, we discover that in Caenorhabditis elegans, the onset of oocyte-to-zygote transition developmentally triggers a rapid mitophagy event. We show that mitophagy at oocyte-to-zygote transition (MOZT) requires mitochondrial fragmentation, the macroautophagy pathway and the mitophagy receptor FUNDC1, but not the prevalent mitophagy factors PINK1 and BNIP3. MOZT reduces the transmission of deleterious mtDNA and as a result, protects embryonic survival. Impaired MOZT drives the increased accumulation of mtDNA mutations across generations, leading to the extinction of descendant populations. Thus, MOZT represents a strategy that preserves mitochondrial health during the mother-to-offspring transmission and safeguards lineage continuity.

DOI: https://doi.org/10.1038/s41556-025-01854-z
Proc Natl Acad Sci U S A. 2026 Jan 20. 123(3): e2526249123

The intrinsic impact of mechanical stress on the maintenance of oocyte dormancy.

Go Nagamatsu, Kenjiro Shirane, Yuzuru Kato, Hiroko Nakamura, Norio Hamada, Kiyoko Kato, Hiroshi Kimura, Katsuhiko Hayashi.

  In the mammalian ovary, most oocytes remain dormant, and their dormant status plays a central role in maintaining the reservoir population of the female germ line. The equilibrium between the dormant and active states, the latter of which is responsible for producing mature oocytes, is therefore crucial for ensuring the sustained reproductive capability of females. We have previously reported that mechanical stress in the ovary plays a crucial role in oocyte dormancy. However, the mechanism underlying this relation remains unclear. Here, we demonstrated that the mechanical stress is directly transduced into the oocytes, rather than to the surrounding granulosa cells. Culture experiments and live-imaging analysis revealed the nuclear localization of FOXO3, a hallmark of oocyte dormancy, within oocytes cultured alone in response to mechanical stress. Interestingly, we found that the cytological response to mechanical stress was accompanied by ligand-independent internalization of the c-kit receptor, which dampens intracellular signaling and prevents oocyte activation. These results shed light on the relation between mechanical stress and oocyte dormancy and provide clues toward a greater understanding of female reproductive capability.

Keywords:  FOXO3; oocyte; ovary

DOI:  https://doi.org/10.1073/pnas.2526249123
Development. 2026 Jan 01. pii: dev205037. [Epub ahead of print]153(1):

MEIOC prevents continued mitotic cycling and promotes meiotic entry during mouse oogenesis.

Esther G Ushuhuda, Jenniluyn T Nguyen, Natalie G Pfaltzgraff, Shelbie M Wenner, Matthew Kofron, Maria M Mikedis.

  To generate haploid gametes, germ cells must transition from mitosis to meiosis. In mammals, the transcriptional activator STRA8-MEIOSIN mediates the decision to enter the meiotic cell cycle, but how germ cells prevent continued mitotic cycling before meiotic entry remains unclear. MEIOC was previously shown to repress the mitotic program after meiotic entry. Here, we investigate the role of MEIOC in the mitosis-to-meiosis transition during mouse oogenesis. Using cell proliferation analysis and cell cycle transcriptomics, we demonstrate that MEIOC prevents continued mitotic cycling prior to meiotic entry in oogenic cells. We find that G1/S cyclin CCNA2 is downregulated during the mitosis-to-meiosis transition, and MEIOC contributes to this downregulation. MEIOC also promotes entry into meiosis by increasing Meiosin transcript abundance and consequently activating STRA8-MEIOSIN. Thus, in mouse oogenic cells, the transition from mitosis to meiosis occurs as two molecularly regulated steps - (1) the halt of mitotic cycling and (2) entry into the meiotic cell cycle - and that MEIOC modifies the cell cycle program to facilitate both steps in this transition.

Keywords:  Fetal oocytes; MEIOC; MEIOSIN; Meiosis; Ovarian germ cell; STRA8

DOI:  https://doi.org/10.1242/dev.205037
FASEB J. 2026 Jan 31. 40(2): e71445

hnRNPU Safeguards Oocyte Development and Female Fertility via Regulation of Alternative Splicing.

Jinmei Li, Bei Chen, Yujiao Wen, Yanqing Wu, Kuan Liu, Jingshou Chen, Shuangqi Wang, Shenglei Feng, Juan Dong.

  RNA-binding proteins (RBPs) are essential for oocyte development, folliculogenesis, and ovarian homeostasis by regulating RNA metabolism. Heterogeneous nuclear ribonucleoprotein U (hnRNPU) plays critical roles in the regulation of multiple physiological processes as a key RBP, yet its function in mammalian oocytes remains poorly understood. Here, we generated two oocyte-specific Hnrnpu knockout mouse models by using Zp3-Cre and Gdf9-Cre transgenic mouse lines to dissect its role in female reproduction. Both models exhibited severe follicular developmental arrest and complete female infertility. Zp3-Cre-mediated deletion caused oocyte arrest at the germinal vesicle (GV) stage, whereas Gdf9-Cre-mediated deletion nearly abolished GV oocyte retrieval, indicating a more severe developmental block and revealing stage-specific requirements for hnRNPU. Mechanistic investigations focused on the Zp3-Cre model, which provided sufficient GV oocytes for molecular analyses. Loss of Hnrnpu in growing oocytes led to mitochondrial dysfunction, impaired oocyte-granulosa cell communication, and increased follicular apoptosis. Transcriptomic profiling revealed widespread dysregulation of genes involved in mitochondrial function and cell adhesion, with numerous mitochondrial-associated transcripts exhibiting aberrant pre-mRNA splicing. Collectively, our findings identify hnRNPU as an indispensable regulator of oocyte development and female fertility, acting through alternative splicing regulation to preserve mitochondrial function, maintain oocyte quality, and support folliculogenesis.

Keywords:  alternative splicing; female; heterogeneous nuclear ribonucleoprotein U; infertility; mitochondria; oocyte

DOI:  https://doi.org/10.1096/fj.202503270R
J Genet Genomics. 2026 Jan 09. pii: S1673-8527(26)00002-0. [Epub ahead of print]

SYMPK interacts with KIF20A and NUMA1 to coordinate spindle organization and safeguard oocyte meiotic maturation.

Bei Chen, Mofan Zhou, Jiaqi Wang, Jinxin Xiao, Yirong Chen, Jinying Wang, Wenlin He, Tianbao Song, Jin Luo, Qingzhen Xie, Cong Liu.

  Mammalian oocyte maturation relies on the precise assembly of the acentrosomal spindle, and its disruption causes aneuploidy and developmental failure. Symplekin (SYMPK), a 3'-end processing scaffold with emerging functions in regulating chromosome dynamics, remains unexplored in oocytes. Here, we investigate whether SYMPK governs spindle dynamics and chromosome fidelity during meiotic maturation. We find SYMPK dynamically tracks spindle microtubules during oocyte maturation following germinal vesicle breakdown (GVBD). By generating oocyte-specific Sympk knockout mice, loss of SYMPK in oocytes yields complete female infertility and impaired oocyte quality. Sympk-deficient oocytes show a predominant metaphase I (MI) arrest, accompanied by disorganized spindle architecture and destabilized kinetochore-microtubule attachments. Furthermore, chromosome spreads indicate persistent spindle assembly checkpoint (SAC) activation, and pharmacologic SAC inhibition can partially restore meiotic progression but not spindle integrity in SYMPK-deficient oocytes. Mechanistically, immunoprecipitation-mass spectrometry in MI oocytes reveals that SYMPK interacts with the spindle regulators KIF20A and NUMA1, and is required for their proper localization to the spindle. Collectively, these findings establish that SYMPK supports KIF20A and NUMA1 to coordinate acentrosomal spindle organization, thereby safeguarding oocyte meiotic maturation and ensuring faithful female meiotic progression.

Keywords:  Female fertility; Meiosis; Oocyte; SYMPK; Spindle organization

DOI:  https://doi.org/10.1016/j.jgg.2026.01.002
iScience. 2026 Jan 16. 29(1): 114416

Balanced DNA-to-cytoplasm ratio at the 2-cell stage is critical for mouse preimplantation development.

Tao Pan, Natsumi Taira, Miho Ohsugi.

  Among vertebrates, mammalian haploid embryos are highly prone to early developmental arrest for reasons that remain unclear. Using mouse preimplantation embryos with altered cell size and ploidy, we show that arrest primarily results from an imbalance between ploidy and cytoplasmic volume, rather than from haploidy itself. Haploid and double-sized diploid embryos exhibit spindle and contractile ring defects, resulting in chromosome nondisjunction and cytokinesis failure beginning at the second mitosis. Reducing cytoplasmic volume to restore the DNA-to-cytoplasm ratio rescues these abnormalities. Delaying the reduction of the DNA-to-cytoplasm ratio until the late 2-cell stage prevents developmental defects, revealing a critical temporal window for this ratio. Moreover, moderate transcriptional inhibition at this stage in normal diploid embryos induces similar errors. Our findings highlight that in mammalian embryos, where major zygotic genome activation occurs in large cells, balance between ploidy and cytoplasmic volume is necessary to sustain sufficient protein levels for mitosis and development.

Keywords:  cell biology; developmental biology; genetics; molecular biology

DOI:  https://doi.org/10.1016/j.isci.2025.114416
bioRxiv. 2025 Dec 03. pii: 2025.12.03.692175. [Epub ahead of print]

Differential contributions of β-tubulin isotypes to acentrosomal oocyte meiosis in C. elegans.

Emmanuel T Nsamba, Anne M Villeneuve.

Oocyte meiotic spindles must achieve bipolarity and segregate chromosomes in the absence of centrosomes. Here we use high-resolution immunofluorescence microscopy and live imaging to investigate the differential contributions of β-tubulin isotypes (TBB-1 and TBB-2) to assembly and function of acentrosomal spindles in Caenorhabditis elegans oocytes. By combining strains with altered β-tubulin isotype composition with mutations affecting microtubule-crosslinking motor KLP-18 and/or mutations affecting katanin-mediated microtubule severing, we show that TBB-1 and TBB-2 make distinct contributions to promoting spindle bipolarity. Further, by measuring multiple spindle features in wild-type and β-tubulin isotype substitution strains, we reveal contributions of isotype composition to spindle morphology, kinetics of anaphase chromosome separation and maintenance of spindle structural integrity under stress. Together, our data support a model in which β-tubulin isotype composition helps to maintain a balance between microtubule crosslinking and severing activities during oocyte meiosis. We further propose that this balance is crucial for establishing spindle bipolarity, maintaining spindle structures, and modulating the dynamics of chromosome separation.

DOI: https://doi.org/10.64898/2025.12.03.692175
Nucleic Acids Res. 2026 Jan 05. pii: gkaf1469. [Epub ahead of print]54(1):

Maternal TDP43 orchestrates nuclear speckle assembly and zygotic splicing activation during oocyte-to-embryo transition in mice.

Zuo-Qi Deng, Zhi-Yan Jiang, Yu-Ke Wu, Yun-Wen Wu, Hua Zhang, Lu Chen, Zhi-Yi Li, Li-Ling Liu, Heng- Yu Fan.

Zygotic splicing activation (ZSA) is a crucial process of mRNA post-transcriptional regulation during maternal-to-zygotic transition, ensuring normal embryonic development. However, the key factors and mechanisms underlying ZSA regulation remain unclear. We observed that the nuclear speckle (NS), a key splicing region, was newly established at the 2-cell stage in mice and was consistent with the ZSA period. Moreover, NS and TAR DNA-binding protein-43 (TDP43) always exhibited a partially adjacent and mutually exclusive localization relationship. TDP43 performed its function through liquid-liquid phase separation. The condensation-deficient state of TDP43 was the active form involved in NS regulation in 2-cell embryos. Additionally, TDP43 could also interact with both transcribed RNAs associated with NS and directly with NS proteins. Maternal TDP43 deficiency led to the failure of NS assembly in 2-cell embryos, resulting in the inability to skip exons during transcript splicing. In contrast, ectopic expression of TDP43 in zygotes led to abnormal enlargement of the NS, resulting in excessive skipping of transcript exons. Both bidirectional ZSA disorders led to 2-cell arrest during early embryogenesis. ZSA defects caused by TDP43 deficiency also impaired cell totipotency-pluripotency conversion. In this study, we identified an NS upstream regulatory factor, TDP43, which helps maintain the balance of ZSA, providing a new perspective on the post-transcriptional regulation of early embryos.

DOI: https://doi.org/10.1093/nar/gkaf1469
Aging Cell. 2026 Feb;25(2): e70374

Decreased PTGES2 Farnesylation in Granulosa Cells Compromises PGE2-Dependent Cumulus Expansion and Oocyte Maturation During Ovarian Aging.

Sainan Zhang, Jiahui Qi, Chuanming Liu, Huidan Zhang, Bichun Guo, Die Wu, Yicen Liu, Xin Zhen, Yang Zhang, Nannan Kang, Jidong Zhou, Guijun Yan, Chaojun Li, Lijun Ding, Haixiang Sun.

  With the increasing trend of delayed childbearing, the decline in oocyte quality associated with advanced maternal age has emerged as a pressing concern. However, the mechanism remains unclear, and effective strategies for improvement are currently lacking. Previously, we reported that the downregulation of the mevalonate pathway in aged granulosa cells (GCs) contributed to meiotic defects in oocytes, which may implicate farnesyl pyrophosphate-mediated protein farnesylation. Nevertheless, the role of farnesylation in ovarian aging and its impact on oocytes requires further investigation. In this study, using cumulus-oocyte complexes (COCs) from young and aged female mice, we observed impaired cumulus expansion and concurrent meiotic defects during aged oocyte maturation, accompanied by significantly reduced protein farnesylation in aged GCs. Furthermore, inhibiting farnesylation with FTI-277 in young COCs recapitulated the aging phenotype, disrupting cumulus expansion and inducing meiotic defects similar to those in aged COCs. Conversely, restoring farnesylation via farnesol supplementation effectively ameliorated these deficits in both aged COCs (in vitro) and aged mice (in vivo). Proteomic analysis and experimental validation identified prostaglandin E2 synthase 2 (PTGES2) as a farnesylated protein. Mechanistically, age-related decline in PTGES2 farnesylation in GCs reduces its endoplasmic reticulum localization and impairs prostaglandin E2 (PGE2) production, thereby compromising PGE2-dependent cumulus expansion and oocyte maturation. Collectively, our findings highlight the detrimental effects of decreased farnesylation in aged GCs on oocyte quality and propose a potential therapeutic strategy for improving the developmental competence of aged oocytes.

Keywords:  PTGES2; cumulus expansion; farnesylation; oocyte maturation; ovarian aging

DOI:  https://doi.org/10.1111/acel.70374
bioRxiv. 2025 Sep 12. pii: 2025.09.11.675685. [Epub ahead of print]

Active maintenance of meiosis-specific chromosome structures in C. elegans by the deubiquitinase DUO-1.

Liesl G Strand, Charlotte P Choi, Savannah McCoy, Emmanuel T Nsamba, Nicola Silva, Anne M Villeneuve.

Meiotic prophase is characterized by a dynamic program in which germ cells undergo a complex series of associations and dissociations of protein complexes that drive assembly, remodeling, and disassembly of meiosis-specific chromosome structures and dramatic changes in chromosome compaction. Failure to properly coordinate these processes can result in improper chromosome segregation, producing aneuploid gametes and inviable zygotes. Here, we investigate the roles of C. elegans DUO-1, an ortholog of mammalian ubiquitin-specific proteases USP26 and USP29, in mediating these dynamic chromosomal events during meiotic prophase. Cytological analyses of duo-1 null mutants indicate that loss of DUO-1 function leads to impaired assembly of synaptonemal complexes (SCs), loss of integrity of meiotic chromosome axes, ineffective homolog pairing, premature separation of sister chromatids, and late-prophase chromosome decompaction. Further, SC instability in duo-1 mutants correlates with depletion of REC-8 cohesin complexes and is accompanied by massive accumulation of early DSB repair intermediates. By using a dual-AID-tagged allele to deplete DUO-1 during meiotic development, we demonstrate that DUO-1 is continually required throughout meiotic prophase progression, to promote proper axis/SC assembly in early prophase, to maintain axis/SC stability during the late pachytene stage, and to promote/maintain chromosome compaction at the end of meiotic prophase. Together, our data reveal that meiotic chromosome structure and meiosis-specific chromosome architecture require active maintenance throughout meiotic prophase, and that this maintenance is necessary for successful meiosis.

DOI: https://doi.org/10.1101/2025.09.11.675685
bioRxiv. 2026 Jan 06. pii: 2026.01.06.697898. [Epub ahead of print]

SLBP-independent control of maternal histone mRNA.

Joana Pereirinha, Martin Brehm, Shamitha Govind, Anke Busch, Nadezda Podvalnaya, Ann-Sophie Seistrup, Kamila Delaney, Florian A Steiner, Julian Konig, Sebastian Falk, René F Ketting.

Replication-dependent (RD) histones are crucial for packaging newly replicated DNA into chromatin, ensuring genome stability. In metazoans, the mRNA of RD histones is uniquely regulated through a conserved 3' stem-loop bound by stem-loop binding protein (SLBP). This allows cell cycle-coupled regulation of these important transcripts. However, oocytes must stabilise histone mRNAs independently of the cell cycle to ensure maternal loading to support the first embryonic divisions. Using Caenorhabditis elegans as a model system, we discovered an SLBP-independent mechanism that ensures RD histone transcript stability during oogenesis. This is mediated by the protein complex PETISCO, bound to the effector protein TOST-1, which directly binds the histone stem-loop region and maintains maternal histone mRNA levels during oogenesis and early embryogenesis. Loss of this mechanism disrupts histone homeostasis, leading to premature genome activation, mitotic defects, and embryonic lethality. Interestingly, the same complex, PETISCO, acts in piRNA biogenesis when bound to the effector PID-1, revealing an intriguing co-option of this histone mRNA homeostasis mechanism by the piRNA pathway. Our findings reveal a unique SLBP-independent mechanism of histone mRNA regulation, that served as a basis for the evolution of a novel piRNA biogenesis mechanism.

DOI: https://doi.org/10.64898/2026.01.06.697898
Nat Commun. 2026 Jan 15.

H3K27me3-dependent imprinting and transcriptional regulation in early mouse embryos requires EZHIP-mediated restriction of PRC2 activity.

Seynabou Diop, Laia Richart, Ambre Petitalot, Juliette Boni, Corentin Mollier, Batuhan Altay, Aurelien Dauphin, Virginie Raynal, Jean-Léon Maître, Katia Ancelin, Raphaël Margueron.

Zygotes inherit parental genomes with distinct chromatin structures. In eutherian mammals, this asymmetry is considered crucial for embryonic development, notably because it enables genomic imprinting. Besides the well-established role of DNA methylation in this process, a transient form of imprinting in mice has been shown to rely instead on H3K27me3. Here, we show that maternal deletion of Ezhip, encoding a negative regulator of PRC2, initially increases the asymmetric distribution of H3K27me3 among the parental genomes at the zygotic stage but subsequently impairs H3K27me3-dependent imprinting and mitigates X-chromosome inactivation in pre-implantation embryos. We show that EZHIP protein, translated from the maternal mRNA pool, is present during the first cell divisions post-fertilization and limits PRC2 enzymatic activity. In its absence, the H3K27me3 landscape is both expanded and flattened, and the asymmetry between the two parental genomes is lost. Our study reveals the deleterious consequences on early embryonic development of unleashing PRC2 activity.

DOI: https://doi.org/10.1038/s41467-026-68467-4
Syst Biol Reprod Med. 2026 Dec;72(1): 73-86

Tracing refractile body biogenesis in human oocytes: the role of lysosomes and mitochondria.

Yuto Aoki, Xingqiang Wei, Mikiya Nakatsuka, Junko Otsuki.

  Refractile bodies (RBs) in human primordial oocytes may represent a lysosomal mechanism of cellular waste management independent of hormonal stimulation or age. This observational study investigated the ultrastructural features and molecular characteristics of refractile bodies (RBs) in human primordial oocytes, focusing on the involvement of lysosomes, autophagy, and mitochondria. Ovarian tissues were obtained from 34 individuals undergoing oophorectomy as part of female-to-male gender-affirming surgery, with no clinical interventions applied. Using fluorescence microscopy, immunocytochemistry, and transmission electron microscopy (TEM), we found large RBs (>5 μm) in all individuals, with no correlation to age. RBs exhibited strong LysoTracker fluorescence, indicating acidic content. LC3, but not RAB7, colocalized with RBs, suggesting incomplete autophagic processing. TEM revealed lysosomal vesicles, mitochondrial remnants, and lipid-rich structures within RBs, some partially enclosed by isolation membranes. These features support a model in which RBs transition from passive lipid accumulation to autophagy-driven remodeling in a size-dependent manner. RBs displayed lipofuscin-like characteristics and are likely formed through lysosomal and mitophagic pathways. Their formation appears to involve both canonical and non-canonical autophagic mechanisms, independent of age or hormonal stimulation. A limitation of this study is its observational nature without functional validation.

Keywords:  Refractile body; autophagy; lipofuscin; lysosome; primordial oocyte

DOI:  https://doi.org/10.1080/19396368.2025.2610348
bioRxiv. 2026 Jan 09. pii: 2026.01.08.698407. [Epub ahead of print]

LOTUS-domain proteins activate Vasa to drive germ granule assembly.

Ian F Price, Chin Wang, Wen Tang.

Germline development relies on perinuclear membraneless germ granules, yet the mechanisms underlying their assembly remain incompletely understood. Here we uncover a conserved and central role for LOTUS-domain proteins in driving germ granule assembly. In C. elegans , the LOTUS-domain protein EGGD-1/MIP-1 at sub-stoichiometric levels recruits Vasa protein GLH-1 to the nuclear periphery. Acting as a catalyst, EGGD-1 impacts the ATPase cycles of GLH-1 by preferentially binding to its open conformation, enhancing its RNA binding activities, and facilitating its transition to the closed conformation. GLH-1 in the closed state enriches mRNAs at the nuclear periphery, which enables the accumulation of RNA-binding proteins including PGL-1 and PGL-3. Using human cells, we demonstrate the LOTUS-domain protein TDRD5 similarly recruits DDX4, the human Vasa homolog, and stimulates the formation of intermitochondrial cement. Collectively, these findings reveal evolutionarily conserved stimulatory effect of LOTUS-domain protein in Vasa activity and provide a unified model for germ granule assembly across species.

DOI: https://doi.org/10.64898/2026.01.08.698407