bims-cebooc 2026-05-03 papers

Issue of 2026–05–03
nine papers selected by
Gabriele Zaffagnini, Universität zu Köln

Nature. 2026 Apr 29.

Cytoplasmic competition between separate parental pronuclei in zygotes.

Hirohisa Kyogoku, Mitsusuke Tarama, Masahiro Matsuwaka, Tappei Mishina, Akihito Harada, Reiko Nakagawa, Mami Kumon, Yoshihiro Shimizu, Yasuyuki Ohkawa, Tatsuo Shibata, Azusa Inoue, Tomoya S Kitajima.

Embryogenesis begins with a zygote-a single cell with two pronuclei that separately enclose maternal and paternal chromosomes. The functional significance of the separation of parental chromosomes into distinct pronuclei remains unexplored, despite the fact that one-pronuclear biparental zygotes are used clinically1-3. Here, using a combination of mouse zygote manipulation, quantitative imaging and theoretical approaches, we show a cytoplasm-mediated competition mechanism between separate parental pronuclei that ensures developmental potential. This mechanism limits pronuclear volume and prevents epigenetic mark dysregulation, including loss of trimethylated histones. One-pronuclear biparental zygotes lack this mechanism, resulting in a reduced rate of development to term. This low developmental potential can be partially rescued by competition-based or drug-based restoration of epigenetic marks. This study provides a spatial mechanism linking fertilization to the establishment of the full developmental potential for the next generation, highlighting caveats in clinical use of one-pronuclear biparental zygotes.

DOI: https://doi.org/10.1038/s41586-026-10417-7

Nat Aging. 2026 Apr 29.

Multimodal data analysis reveals asynchronous aging dynamics across female reproductive organs.

Oleksandra Soldatkina, Laura Ventura-San Pedro, Natàlia Pujol-Gualdo, Allal El Hommad, Jose Miguel Ramirez, Aida Ripoll-Cladellas, Maria Sopena-Rios, Daniel Tabares, Miguel Ángel Pérez-Elena, David Torrents, Jaume Ordi, Marta Melé.

Female reproductive aging has systemic health implications, yet tissue-level dynamics remain poorly understood. Here we integrate deep learning analysis of 1,112 histology images with RNA sequencing from 659 samples across seven female reproductive organs in donors aged 20-70 years. We uncover asynchronous trajectories: the ovary ages gradually, whereas the uterus shows an abrupt molecular and morphological shift around menopause. This uterine transition is independently supported by plasma proteomics data from a large population cohort, indicating that organ-linked aging signatures are detectable in circulation. Tissue segmentation highlights the myometrium as strongly age affected, with extracellular matrix remodeling and immune activation. Epithelial tissues also show coordinated age-related remodeling, with a sharp menopausal transition in the vaginal epithelium. Multi-omics factor analysis links these histological changes to nonlinear gene-expression shifts enriched for reproductive traits, including pelvic organ prolapse and age at menarche. Together, these findings establish menopause as a key inflection point in female aging and provide a tissue-resolved, multi-dataset framework for late-life health.

DOI: https://doi.org/10.1038/s43587-026-01098-y

Biol Reprod. 2026 Apr 25. pii: ioag086. [Epub ahead of print]

Molecular basis of chromosome segregation and age-associated errors in oocyte meiosis I.

Tomoya S Kitajima.

Oocyte meiosis determines chromosomes that are transmitted from the mother to the next generation. The molecular mechanisms underlying meiotic chromosome segregation are organized in distinct chromosomal regions-the core centromere, peri-centromere, and chromosome arms. A common molecular basis for mechanisms operating in these distinct regions is Rec8 cohesin, together with cooperating regulatory pathways. This Review describes Rec8-cohesin-based mechanisms operating in each chromosomal region and discusses how these mechanisms work coordinately to achieve chromosome segregation during meiosis I, focusing primarily on insights from studies using mouse oocytes as a model system. Based on this molecular understanding, it further discusses how age-associated decline of chromosomal Rec8 cohesin can lead to chromosome segregation errors, a major cause of infertility, miscarriage, and congenital disorders.

DOI: https://doi.org/10.1093/biolre/ioag086

Aging Cell. 2026 May;25(5): e70529

A Decline in Follicle Cell Function Is a Major Driver of Drosophila Ovarian Aging.

Emily A Wolfgram, Todd G Nystul.

The ovary is one of the first organs to lose functionality with age. We found that aging of the Drosophila ovary is characterized by an accumulation of phenotypes in the somatic compartment, including failure of the follicle cells to encapsulate germ-cell cysts, an extended S phase, and increased DNA damage. In aged ovaries, follicle encapsulation defects are associated with the lack of a germ-cell cyst checkpoint in early oogenesis. Single-cell RNA sequencing revealed that, across all cell types in the ovary, cells in the follicle lineage have the highest number of differentially expressed genes. Overexpression of Atg8a, a key autophagy machinery gene homologous to mammalian LC3, specifically in follicle cells prevents age-associated decline in the follicle epithelium and loss of reproductive capacity. Collectively, these findings demonstrate that genetic manipulation of a small population of ovarian somatic cells is sufficient to improve both cell-autonomous and non-autonomous features of reproductive aging.

Keywords: drosophila ; aging; cell biology; ovary; reproduction

DOI: https://doi.org/10.1111/acel.70529

Nat Commun. 2026 Apr 30.

Deciphering tRNA repertoires and translation coordination during mouse early embryogenesis by ORACLE-tRNAseq.

Yun Li, Xin Wang, Ruofan Huang, Haoquan Yu, You Wu, Ze Shu, Wenlin Jiang, Zheng Cao, Zongyu Yu, Hongyan Li, Rushuang Yan, Yawei Gao, Xiao-Ou Zhang, Yunfang Zhang.

Translational control is vital during the maternal-to-zygotic transition (MZT), yet the landscape of embryonic transfer RNA (tRNA) pools has been difficult to explore. Here, we develop Optimized Reaction for Accurate Capture of Low-input Entities tRNA Sequencing (ORACLE-tRNAseq), enabling robust tRNA profiling from as few as five mouse oocytes. We map tRNA landscapes from oocyte to blastocyst, identifying a distinct transition to embryonic tRNA repertoires and upregulation of tRNA pseudogenes at the 4-cell stage. Integrated multi-omics analyses reveal that zygotic tRNA gene activation coincides with zygotic genome activation (ZGA) and correlates with H3K4me3 establishment and chromatin remodeling. By coupling ORACLE-tRNAseq with Ribo-seq, we demonstrate that embryonic tRNA anticodon pools coordinate with high translation-efficiency gene pools to preferentially establish the zygotic translation machinery, particularly from major ZGA onwards. Collectively, these findings provide a resource for understanding translational regulatory networks during early embryogenesis.

DOI: https://doi.org/10.1038/s41467-026-72603-5

Nat Commun. 2026 Apr 29.

Uridine restores oocyte quality and mitigates female reproductive aging by inhibition of ferroptosis in mice.

Jingyue Chen, Jianing Shen, Dongxu Li, Guangjun Huang, Rui Wang, Xiaofan Sun, Meijie Chen, Tianyi Liao, Liying Yan, Peng Yuan, Bo Xiong, Jie Qiao.

Advanced maternal age is a key factor in female infertility, primarily due to declines in ovarian reserve and oocyte quality. However, the metabolic mechanisms underlying reproductive aging remain unclear. Here, we show that uridine levels in the plasma and ovaries of aged mice are significantly reduced compared with young controls. Building on this, we find that uridine supplementation significantly improves meiotic maturation, fertilization, and early embryonic development of aged oocytes, both in vivo and in vitro. Further microtranscriptomic analyses reveal that uridine enhances oocyte quality by inhibiting ferroptosis and enhancing mitochondrial function. Moreover, by integrating Limited Proteolysis-Small Molecule Mapping, western blotting and siRNA-based functional assays, we identify that uridine binds to poly(rC)-binding protein 1, thereby suppressing ferroptosis and preserving mitochondrial function. Collectively, these findings demonstrate that uridine supplementation improves fertility in aged female mice and provide mechanistic insight into ferroptosis in oocyte aging.

DOI: https://doi.org/10.1038/s41467-026-72406-8

Biol Reprod. 2026 Apr 30. pii: ioag093. [Epub ahead of print]

Beware of your "oocyte specific" Cre line: somatic cell Cre expression in several Zp3-Cre lines and the Gdf9-iCre transgenic line†.

Paula Stein, Chihiro Emori, Elizabeth Padilla-Banks, Lenka Radonova, Artiom Gruzdev, Masahito Ikawa, Carmen J Williams.

Several zona pellucida 3 (Zp3)-Cre driver mouse lines are used to enable conditional loss-of-function studies in oocytes. The Knowles Zp3-Cre line, currently maintained live at the Jackson Laboratory, is the most widely published. We recently found that the transgene expressed in the Knowles line contains a truncated metallothionein (Mt1) sequence that is expressed at high levels in oocytes from transgenic mice. This finding led us to search for an alternative Zp3-Cre line that did not express an exogenous Mt1 transcript. We tested a second transgenic Zp3-Cre line and then created our own transgenic Zp3-Cre line, neither of which was oocyte-specific as documented by crossing to the tdTomato reporter line. Similar testing confirmed the exquisite oocyte specificity of the Knowles Zp3-Cre line. An alternative to Zp3-Cre is to use the Gdf9-iCre line, which is reported to be oocyte-specific and expressed beginning at the primordial follicle stage. This line similarly showed high somatic tissue Cre expression. Reasoning that a knock-in approach would ensure oocyte specificity, we used a CRISPR/Cas9 approach to insert Cre into the endogenous Zp3 locus. However, crosses of this knock-in line with tdTomato females revealed high somatic tissue expression. Both the Zp3-Cre knock-in and Gdf9-iCre alleles, when paternally inherited, induced Cre expression by the blastocyst stage, explaining the broad tissue distribution. We conclude that the Knowles Zp3-Cre transgenic line remains the best model for generating oocyte-specific expression, though investigators should be aware of the spurious Mt1 expression from the transgene.

Keywords: Gdf9-iCre; Oocyte; Zp3-cre; conditional knockout; transgenic

DOI: https://doi.org/10.1093/biolre/ioag093

Hum Reprod. 2026 May 01. pii: deag073. [Epub ahead of print]

Single-cell proteomics reveals cytoplasmic defects in Patl2-deficient oocytes rescued by spindle transfer.

A Cardona Barberán, E Araftpoor, A Christodoulaki, M Fakhar-I-Adil, J Goethals, A Rybouchkin, C Arnoult, A Boel, M Bühler, K C Pavani, D Stoop, K Gevaert, F Vanden Meerschaut, B Heindryckx.

STUDY QUESTION: Can single-cell, mass spectrometry-based proteomics identify proteins associated with reduced developmental competence of Patl2-/- Metaphase II (MII) mouse oocytes and reveal therapeutic targets for Patl2-related infertility?
SUMMARY ANSWER: Abnormal protein content is detected in Patl2-/- MII oocytes, which can be rescued by spindle transfer (ST).
WHAT IS KNOWN ALREADY: PATL2 is an RNA-binding protein that represses maternal mRNA translation during oocyte maturation. PATL2 mutations in humans often cause germinal vesicle (GV) arrest, although some affected patients produce MII oocytes with reduced fertilization and embryo developmental potential. Consequently, oocyte donation is required. The Patl2-/- knockout mouse model offers a unique opportunity to study Patl2-related infertility and evaluate potential treatments.
STUDY DESIGN, SIZE, DURATION: Patl2 -/- mice (C57BL/6NTac-Patl2tm1a), with deletion of exon 7, were bred from April 2021 to October 2023, yielding 36 homozygous females from 271 pups. To investigate the role of Patl2 at the MII stage, in vivo MII oocytes from Patl2-/- and Patl2+/+ females were collected for analysis of key quality markers and single-cell proteomics. Based on these results, maternal ST was tested to rescue abnormal embryo development. At least three replicates were conducted per experiment.
PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Four- to 12-week-old mice underwent superovulation and oocyte collection to assess in vitro and in vivo maturation. In vivo-matured MII oocytes were used to evaluate activation (AR) and blastocyst rates (BR) after PIEZO-ICSI, spindle configuration, and calcium oscillatory patterns following SrCl2 exposure. Vitrified-warmed oocytes were used for single-cell proteomics using a timsTOF ultra mass spectrometer operated in diaPASEF mode. ST involved transferring the Patl2-/- spindle to Patl2+/+ enucleated cytoplasm, followed by parthenogenetic activation (PA) via SrCl2 exposure.
MAIN RESULTS AND THE ROLE OF CHANCE: Patl2 -/- females exhibit lower in vivo MII rates (79.63%) than Patl2+/+ females (89.39%, P = 0.0123) but similar in vitro maturation rates (GV-MII = 48.74%) compared to Patl2+/+ females (52.85%, P = 0.5230). After PIEZO-ICSI with wild-type sperm, reduced AR (Patl2-/- = 31.71%, Patl2+/+ = 76.74%, P < 0.0001) and BR (Patl2-/- = 7.69%, Patl2+/+ = 42.42%, P = 0.0237) were observed in knockout oocytes. However, Patl2-/- oocytes exhibited normal spindle rates (78.57%) as seen in Patl2+/+ oocytes (86.00%, P = 0.3491), as well as a similar capacity to sustain long-lasting calcium oscillations (A×F = 6.15 ± 4.80) compared to Patl2+/+ oocytes (A×F = 4.59 ± 2.96, P = 0.1453). Single-cell proteomics identified 4882 proteins and confirmed the absence of Patl2 in knockout oocytes, from analyzing 25 Patl2+/+ and 27 Patl2-/- MII oocytes. After filtering, 3747 proteins were used for statistical analysis, revealing 1508 differentially expressed proteins (q-value < 0.05; 992 downregulated, 516 upregulated in Patl2-/- oocytes). The levels of multiple RNA-binding proteins, some of which are proposed Patl2 interactors (Cpeb1, Eif4e1b), were found to be significantly reduced in Patl2-/- oocytes. Additionally, the protein products of several maternal effect genes (MEGs) implicated in mRNA regulation (Zar1, Igf2bp2) and cell cycle division (Tcl1a, Cdk1, Mos) were downregulated, while MEGs participating in epigenetic modifications (Zfp57, Trim28) were upregulated in the knockout group. Consistent with these observations, ST-PA treatment significantly increased AR (100%) and BR (75%) in the Patl2-/- oocytes in comparison to PA alone (AR = 75.95%, P = 0.0078; BR = 45.00%, P = 0.0128), effectively rescuing development to wild-type levels. Lastly, ST-PA treatment did not alter embryonic development in Patl2+/+ oocytes and produced outcomes comparable to PA alone, supporting the technical safety and applicability of the technique.
LARGE SCALE DATA: The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE massIVE partner repository with the dataset identifier MSV000100606.
LIMITATIONS, REASONS FOR CAUTION: Patl2 -/- mice exhibit a less severe phenotype compared to patients carrying PATL2 variants. Patl2-/- female mice display a high MII rate without significant spindle abnormalities, which contrasts with a previously published report. Additionally, ST treatment was conducted using parthenogenetically activated oocytes, rather than biparental embryos.
WIDER IMPLICATIONS OF THE FINDINGS: ST represents a promising treatment for PATL2-related female infertility in patients with MII oocytes, as it appears to restore cytoplasmic defects linked to abnormal RNA-binding proteins and MEGs identified by single-cell proteomics. In contrast, other proposed treatments for poor embryo development, such as assisted oocyte activation, is unlikely to be effective since Patl2-/- oocytes show a normal calcium response.
STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Special Research Fund (BOF) (starting grant BOF.STG.2021.0042.01 awarded to B.H.) and the Research Foundation-Flanders (FWO) (fellowship 1177425 N awarded to E.A.). B.H. has been receiving unrestricted educational funding from Ferring Pharmaceuticals (Aalst, Belgium). A.C.B., E.A., A.C., M.F-I-A., J.G., A.R., M.B., A.B., C.A., K.C.P., D.S., K.G., and F.V.M. have nothing to disclose. B.H. reports being board member of the Belgian Ethical Committee on embryo research.

Keywords: Patl2 −/− mouse model; maternal effect genes; maternal mRNA regulation; maternal spindle transfer; single-cell proteomics

DOI: https://doi.org/10.1093/humrep/deag073

PLoS Genet. 2026 Apr;22(4): e1012129

The pos-1 3' untranslated region governs germline specification and proliferation to ensure reproductive robustness.

Haik V Varderesian, Juliet N Utaegbulam, Hannah E Brown, Beverly Ramirez, Melina Velcani, Sean P Ryder.

During fertilization, haploid gametes combine to form a zygote. The male (sperm) and female (oocyte) gametes contribute a similar amount of DNA, but the oocyte contributes nearly all the cytoplasm. Oocytes are loaded with maternal mRNAs thought to be essential for embryonic patterning after fertilization. A conserved suite of RNA-binding proteins (RBPs) regulates the spatiotemporal translation and stability of maternal mRNAs. POS-1 is a CCCH-type tandem zinc finger RBP expressed in fertilized Caenorhabditis elegans zygotes from maternally supplied mRNA. POS-1 accumulates in the posterior of the embryo where it promotes posterior cell fate. Here, we show that the pos-1 3' untranslated region (UTR) is essential for POS-1 patterning and contributes to maximal reproductive fecundity. We engineered a pos-1 mutant where most of the endogenous pos-1 3'UTR was removed using CRISPR genome editing. Our results show that the 3'UTR represses POS-1 expression in the maternal germline but increases POS-1 protein levels in embryos after fertilization. In a wild-type background, POS-1 repression via the 3'UTR has little impact on fertility. In a sensitized background, the deletion mutant has a complex pleiotropic phenotype where most adult homozygous progeny lack either one or both gonad arms. Most phenotypes become more penetrant at elevated temperature. Together, our results support an emerging model where the 3'UTRs of maternal transcripts, rather than being essential, contribute to reproductive robustness during stress.

DOI: https://doi.org/10.1371/journal.pgen.1012129