bims-cebooc Biomed News
on Cell biology of oocytes
Issue of 2025–09–28
twenty-one papers selected by
Gabriele Zaffagnini, Universität zu Köln
  1. Non-muscle myosin II-dependent cumulus cell migration at ovulation is required for sperm to reach the egg in mice.
  2. Maternal CENP-C restores centromere symmetry in mammalian zygotes to ensure proper chromosome segregation.
  3. Spatiotemporal dynamics and selectivity of mRNA translation during mouse pre-implantation development.
  4. Oocyte surface proteins EGG-1 and EGG-2 are required for eggshell integrity in Caenorhabditis elegans.
  5. Protecting double Holliday junctions ensures crossing over during meiosis.
  6. Holliday junction-ZMM protein feedback enables meiotic crossover assurance.
  7. PINK1 functions in mitophagy and mitochondrial homeostasis during mice oocyte maturation.
  8. Distinct requirements for the C. elegans Delta ligand APX-1 in embryonic viability and adult fertility.
  9. Single-cell-scale spatial transcriptome of the developing and adult mouse ovary.
  10. The microbiota extends the reproductive lifespan of mice by safeguarding the ovarian reserve.
  11. Defining the roles of the Integrator, NEXT, and nuclear exosome complexes in Drosophila oogenesis.
  12. The functional organization of chromosome territories in single nuclei during zygotic genome activation.
  13. A parent-of-origin effect on embryonic telomere elongation determines telomere length inheritance.
  14. Damage-induced phosphorylation of BRC-1/BRD-1 in meiosis preserves germline integrity.
  15. Three lncRNAs promote PUM protein condensation and germline differentiation.
  16. Dynamics of YAP localization and transcript activity in human oocytes and granulosa cells across early-stage folliculogenesis: an exploratory investigation.
  17. Crossover designation recruits condensin to reorganize the meiotic chromosome axis.
  18. Sperm meet the elevated energy demands to attain fertilization competence by increasing flux through aldolase.
  19. Biomarkers of female reproductive aging in gerotherapeutic clinical trials.
  20. Loss of inhibin negative feedback to pituitary gonadotropes leads to enhanced ovulation but pregnancy failure in mice.
  21. Genetic landscape of human oocyte/embryo defects.
  1. Commun Biol. 2025 Sep 24. 8(1): 1357
    Non-muscle myosin II-dependent cumulus cell migration at ovulation is required for sperm to reach the egg in mice.
    Karen Freire Carvalho, Hugh J Clarke.
      At ovulation in mammals, epidermal growth factor (EGFR) signaling in the cumulus granulosa cells that enclose the egg causes them to generate an extracellular matrix and become dispersed within it. This process, termed expansion, is required for sperm to reach the egg. The extracellular signal-related kinase (ERK) pathway mediates matrix production, but the mechanism responsible for cell dispersion is poorly understood. We show that EGFR signaling activates non-muscle myosin II (NMII) in the cumulus cells and that NMII activity is required for full expansion. NMII activation does not require ERK signaling, but instead depends on the Rho-associated coiled-coil containing kinases (ROCK) and the myotonic dystrophy kinase-related CDC42-binding kinases (MRCK). Blocking ROCK or MRCK impairs the ability of the cumulus cells to migrate and reduces the number of sperm that penetrate through the cumulus layer to reach the oocyte. EGFR thus promotes cumulus layer expansion by integrating ERK-dependent production of the matrix with NMII-dependent migration of the cumulus cells within it.
    DOI:  https://doi.org/10.1038/s42003-025-08736-y
  2. Dev Cell. 2025 Sep 24. pii: S1534-5807(25)00537-4. [Epub ahead of print]
    Maternal CENP-C restores centromere symmetry in mammalian zygotes to ensure proper chromosome segregation.
    Catherine A Tower, Gabriel Manske, Emily L Ferrell, Dilara N Anbarci, Kelsey Jorgensen, Binbin Ma, Mansour Aboelenain, Rajesh Ranjan, Saikat Chakraborty, Lindsay Moritz, Arunika Das, Michele Boiani, Ben E Black, Shawn Chavez, Erica E Marsh, Ariella Shikanov, Karen Schindler, Xin Chen, Saher Sue Hammoud.
      Across metazoan species, the centromere-specific histone variant CENP-A is essential for accurate chromosome segregation, yet its regulation during the mammalian parental-to-zygote transition is poorly understood. To address this, we generated a CENP-A-mScarlet mouse model that revealed sex-specific dynamics: mature sperm retain 10% of the CENP-A levels present in MII oocytes. However, this difference is resolved in zygotes prior to the first mitosis, using maternally inherited cytoplasmic CENP-A. Notably, the increase in CENP-A at paternal centromeres is independent of sensing CENP-A asymmetry or the presence of maternal chromosomes. Instead, CENP-A equalization relies on the asymmetric recruitment of maternal CENP-C to paternal centromeres. Depletion of maternal CENP-A decreases total CENP-A in both pronuclei without disrupting equalization. In contrast, reducing maternal CENP-C or disruption of its dimerization function impairs CENP-A equalization and chromosome segregation. Therefore, maternal CENP-C acts as a key epigenetic regulator that resets centromeric symmetry at fertilization to preserve genome integrity.
    Keywords:  CENP-A; CENP-C; MIS18BP1; centromere; epigenetics; intergenerational; mouse; oocyte; sperm; zygote
    DOI:  https://doi.org/10.1016/j.devcel.2025.08.017
  3. Nucleic Acids Res. 2025 Sep 23. pii: gkaf956. [Epub ahead of print]53(18):
    Spatiotemporal dynamics and selectivity of mRNA translation during mouse pre-implantation development.
    Hao Ming, Rajan Iyyappan, Kianoush Kakavand, Michal Dvoran, Andrej Susor, Zongliang Jiang.
      Translational regulation plays a pivotal role during pre-implantation development. However, the mechanisms by which messenger RNAs (mRNAs) are selectively regulated over time, along with their dynamic utilization and fate during this period, remain largely unknown. Here, we performed fraction-resolved polysome profiling and characterized translational dynamics across oocytes and early embryo development. This approach allowed us to examine the changes in translation during pre-implantation development in high resolution and uncover previously unrecognized modes of translational selectivity. We observed a stage-specific delay in translation, characterized by the postponed recruitment of stored mRNAs-either unbound or associated with light ribosomal fractions-into actively translating polysomes (heavy fraction). Comparative analysis of translatome with proteomics, RNA N6-methyladenosine modifications, and mRNA features further revealed both coordinated and distinct regulatory mechanisms during pre-implantation development. Furthermore, we identified a eukaryotic initiation factor 1A domain containing 3, Eif1ad3, which is exclusively translated at the two-cell stage and is essential for embryonic development by regulating ribosome biogenesis and protein synthesis. Collectively, our study provides a valuable resource of spatiotemporal translational regulation in mammalian pre-implantation development and highlights a previously uncharacterized translation initiation factor critical for early embryos.
    DOI:  https://doi.org/10.1093/nar/gkaf956
  4. bioRxiv. 2025 Sep 15. pii: 2025.09.12.675948. [Epub ahead of print]
    Oocyte surface proteins EGG-1 and EGG-2 are required for eggshell integrity in Caenorhabditis elegans.
    Ji Kent Kwah, Shannon Pfeiffer, Mst Gitika Khanom, Aimee Jaramillo-Lambert.
      Metazoan eggs are surrounded by a specialized coat of extracellular matrix that mediates sperm-egg interactions. This coat is rapidly remodeled after fertilization to form a barrier that prevents polyspermy, protects against environmental insults, and provides structural support to the developing embryo. In C. elegans several oocyte surface proteins have been identified that mediate these events. However, whether two of these proteins, EGG-1 and EGG-2, are required for fertilization or downstream events has been unclear. Here, we address this question using more recent advances in genome editing tools through the creation of egg-1 egg-2 deletions of the endogenous loci. We found that egg-1 egg-2 oocytes are fertilization competent and form rudimentary eggshells. While the integrity of the egg-1 egg-2 eggshells are compromised and often rupture within the uterus, surprisingly, some embryos are capable of undergoing several rounds of cell division. Overall, our findings demonstrate that EGG-1 and EGG-2 are not required for fertilization but are involved in post-fertilization processes.
    DOI:  https://doi.org/10.1101/2025.09.12.675948
  5. Nature. 2025 Sep 24.
    Protecting double Holliday junctions ensures crossing over during meiosis.
    Shangming Tang, Sara Hariri, Regina Bohn, John E McCarthy, Jennifer Koo, Mohammad Pourhosseinzadeh, Emerald Nguyen, Natalie Liu, Christopher Ma, Hanyu Lu, Monica Lee, Neil Hunter.
      Chromosomal linkages formed through crossover recombination are essential for the accurate segregation of homologous chromosomes during meiosis1. The DNA events of recombination are linked to structural components of meiotic chromosomes2. Imperatively, the biased resolution of double Holliday junction (dHJ) intermediates into crossovers3,4 occurs within the synaptonemal complex (SC), the meiosis-specific structure that mediates end-to-end synapsis of homologues during the pachytene stage5,6. However, the role of the SC in crossover-specific dHJ resolution remains unclear. Here we show that key SC components function through dependent and interdependent relationships to protect dHJs from aberrant dissolution into non-crossover products. Conditional ablation experiments reveal that cohesin, the core of SC lateral elements, is required to maintain both synapsis and dHJ-associated crossover recombination complexes (CRCs) during pachytene. The SC central region transverse-filament protein is also required to maintain CRCs. Reciprocally, the stability of the SC central region requires the continuous presence of CRCs effectively coupling synapsis to dHJ formation and desynapsis to resolution. However, dHJ protection and CRC maintenance can occur without end-to-end homologue synapsis mediated by the central element of the SC central region. We conclude that local ensembles of SC components are sufficient to enable crossover-specific dHJ resolution to ensure the linkage and segregation of homologous chromosomes.
    DOI:  https://doi.org/10.1038/s41586-025-09555-1
  6. Nature. 2025 Sep 24.
    Holliday junction-ZMM protein feedback enables meiotic crossover assurance.
    Adrian Henggeler, Lucija Orlić, Daniel Velikov, Joao Matos.
      Holliday junctions (HJs) are branched four-way DNA structures that link recombining chromosomes during double-strand break repair1. Despite posing a risk to chromosome segregation, HJs accumulate during meiotic prophase I as intermediates in the process of crossing-over2,3. Whether HJs have additional regulatory functions remains unclear. Here we establish an experimental system in budding yeast that enables conditional nucleolytic resolution of HJs after the establishment of meiotic chromosome synapsis. We find that HJ resolution triggers complete disassembly of the synaptonemal complex without disrupting the axis-loop organization of chromosomes. Mechanistically, HJs mediate the continued association of ZMM proteins with recombination nodules that form at the axes interface of homologous chromosome pairs. ZMM proteins, in turn, promote polymerization of the synaptonemal complex while simultaneously protecting HJs from processing by non-crossover pathways. Thus, reciprocal feedback between ZMMs, which stabilize HJs, and HJs, which retain ZMM proteins at future crossover sites, maintains chromosome synapsis until HJ-resolving enzymes are activated during exit from prophase I. Notably, by polymerizing and maintaining the synaptonemal complex structure, the HJ-ZMM interplay suppresses de novo double-strand break formation and recombination reinitiation. In doing so, this interplay suppresses the DNA damage response, enabling meiotic progression without unrepaired breaks and supporting crossover assurance.
    DOI:  https://doi.org/10.1038/s41586-025-09559-x
  7. Cell Biosci. 2025 Sep 26. 15(1): 126
    PINK1 functions in mitophagy and mitochondrial homeostasis during mice oocyte maturation.
    Shiwei Wang, Xuan Wu, Mengmeng Zhang, Yixiao Zhu, Yajun Guo, Shuang Song, Shenming Zeng.
       BACKGROUND: As a serine/threonine kinase, PINK1 (PTEN-induced putative kinase 1) is widely expressed in mammalian tissues and cells, especially in the female reproductive system. However, its role in meiotic oocytes remains obscure. Here, we report that murine oocytes overexpressing Pink1 are unable to completely progress through meiosis.
    RESULTS: In the present study, we found that PINK1 protein levels in aged oocytes showed a substantial increase. Importantly, we revealed that murine oocytes overexpressing Pink1 are unable to completely progress through meiosis. This leads to inadequate mitochondrial redistribution, an elevated reactive oxygen species (ROS) level, severely disrupted spindle/chromosome organization, and abnormal mitophagy. Furthermore, we noted that elevated Pink1 expression significantly compromises the developmental ability of the mouse early embryo. In addition, we revealed that RAB8A activity is a key factor for PINK1-mediated mitophagy in old oocytes and active guanosine triphosphate (GTP)-bound state RAB8A could partially rescue the quality of aged oocytes by promoting the formation of autolysosome.
    CONCLUSIONS: Collectively, our data display critical functions for PINK1 in meiotic progression and mitochondrial homeostasis in murine oocytes, and RAB8A activity is required for PINK1-mediated mitophagy in senescent oocytes.
    Keywords:  Mitochondrial homeostasis; Mitophagy; Oocyte; PINK1; RAB8A
    DOI:  https://doi.org/10.1186/s13578-025-01460-4
  8. G3 (Bethesda). 2025 Sep 26. pii: jkaf229. [Epub ahead of print]
    Distinct requirements for the C. elegans Delta ligand APX-1 in embryonic viability and adult fertility.
    Chien-Hui Chuang, Erin Z Aprison, Ilya Ruvinsky, Bruce Bowerman.
      Requirements for the C. elegans Notch ligand APX-1 have been described, but the molecular lesions in mutant alleles remain unknown. Here we report the sequence changes in three previously isolated non-conditional alleles and two newly isolated alleles, apx-1(or545ts) and a null allele apx-1(or2015). All alleles resulted in highly penetrant embryonic lethality but only null mutations greatly reduced brood sizes. This reproductive phenotype was likely due to abnormal ovulation rupturing oocytes and, together with vulva defects, resulting in debris accumulation that prevented embryo passage. In addition to identifying molecular lesions in apx-1 alleles and clarifying distinct requirements for C. elegans Notch ligands, our results reveal extensive genotype-by-environment interactions, including haploinsufficiency of essential loci at a stressfully high growth temperature, and highlight the origins of complex phenotypes as a consequence of multiple seemingly unrelated defects.
    Keywords:  Delta; Notch; embryogenesis; fertility; haploinsufficiency; ovulation; signaling; vulva development
    DOI:  https://doi.org/10.1093/g3journal/jkaf229
  9. bioRxiv. 2025 Sep 17. pii: 2025.09.16.676655. [Epub ahead of print]
    Single-cell-scale spatial transcriptome of the developing and adult mouse ovary.
    Anthony S Martinez, Tyler J Gibson, Jennifer McKey.
      Mammalian ovary development is essential for female fertility, involving the complex spatial patterning of diverse cell types to establish the finite reserve of ovarian follicles. While single-cell transcriptome analyses have provided important insights into the mechanisms driving specification and developmental trajectories of ovarian cells, they disrupt this crucial spatial context. To overcome this limitation, we used 10X Genomics Visium HD spatial transcriptomics to analyze the developing mouse ovary while maintaining its native cellular architecture. We captured all ovarian cell types at eight key fetal and postnatal timepoints, generating a near single cell resolution library of spatial gene expression across ovarian development. This comprehensive dataset allows analysis of dynamic transcriptional signatures associated with unique spatial patterning throughout development, including the establishment of cortex and medulla and assembly of ovarian follicles in each region. This dataset represents a fundamental resource for the investigation of regulatory mechanisms driving spatial patterning of the ovary and opens new avenues to explore the spatial determinants of female fertility and reproductive longevity.
    Short narrative: This report describes a near-single-cell map of spatially resolved gene expression in the developing mouse ovary using 10X Genomics Visium HD, preserving the crucial cellular architecture that is lost in traditional single-cell analyses. This comprehensive dataset, covering eight key developmental timepoints, provides a fundamental resource for investigating how spatial patterning regulates critical ovarian events like follicle assembly.
    DOI:  https://doi.org/10.1101/2025.09.16.676655
  10. Cell Host Microbe. 2025 Sep 25. pii: S1931-3128(25)00372-5. [Epub ahead of print]
    The microbiota extends the reproductive lifespan of mice by safeguarding the ovarian reserve.
    Sarah K Munyoki, Julie P Goff, Amanda Reshke, Erin Wilderoter, Nyasha Mafarachisi, Antonija Kolobaric, Yi Sheng, Steven J Mullett, Gabrielle E King, Jacob D DeSchepper, Richard J Bookser, Carlos A Castro, Stacy L Gelhaus, Mayara Grizotte-Lake, Kathleen E Morrison, Anthony J Zeleznik, Timothy W Hand, Miguel A Brieño-Enriquez, Eldin Jašarević.
      Infertility affects one in six people, but the underlying mechanisms remain unclear. We show that the microbiota governs female reproductive longevity in mice. Germ-free mice have fewer primordial follicles, increased atresia, and ovarian fibrosis, leading to smaller litters, fewer offspring, and a shorter reproductive lifespan. Germ-free mice are born with a similar ovarian reserve but display excessive activation, impaired progression, and increased atresia during post-natal development. Microbiome colonization during a critical post-natal window rescues premature ovarian reserve loss by normalizing follicle kinetics and gene expression patterns. These changes parallel increased short-chain fatty acids (SCFAs), and SCFA administration mitigates ovarian dysfunction in germ-free mice. Similar oocyte dysfunction occurred in conventionally raised mice fed a high-fat diet, but additional dietary fiber helped preserve oocyte quality and embryo competence. Thus, host-microbe interactions shape female fertility, and microbiota-targeted interventions may offer strategies to address reproductive disorders.
    Keywords:  dietary fiber; fertility; ovarian reserve; reproductive lifespan; weaning reaction
    DOI:  https://doi.org/10.1016/j.chom.2025.09.006
  11. Cell Rep. 2025 Sep 23. pii: S2211-1247(25)01100-3. [Epub ahead of print]44(10): 116329
    Defining the roles of the Integrator, NEXT, and nuclear exosome complexes in Drosophila oogenesis.
    Yongjin Lee, Adriano Biasini, Cindy Tipping, Seong Hyeon Hong, Phillip D Zamore.
      Nuclear RNA homeostasis depends on the balance of transcription, RNA processing, degradation, and transport between the nucleus and cytoplasm. RNA degradation directed by the Integrator, nuclear exosome targeting (NEXT), and nuclear exosome complexes controls the accumulation of aberrant nuclear RNA. Here, we report that Drosophila oogenesis requires the Integrator, NEXT, and nuclear exosome complexes. Depletion of Integrator, NEXT, or nuclear exosome components in Drosophila female germ cells causes infertility and accumulation of 3' extended small nuclear RNAs, promoter upstream transcripts, and cryptic transcripts. Our data highlight the essential role of nuclear RNA degradation and processing in Drosophila oogenesis and provide a catalog of RNAs whose nuclear levels are regulated by these three complexes. We propose that Integrator, NEXT, and the nuclear exosome support oogenesis by ensuring that inappropriate transcription does not overwhelm the limited supply of proteins that bind, process, and traffic RNA.
    Keywords:  Ars2; CP: Molecular biology; Dis3; IntS11; Integrator; NEXT; Rrp6; ZC3H18; cryptic transcripts; nuclear exosome; small nuclear RNA
    DOI:  https://doi.org/10.1016/j.celrep.2025.116329
  12. bioRxiv. 2025 Apr 06. pii: 2025.04.06.647428. [Epub ahead of print]
    The functional organization of chromosome territories in single nuclei during zygotic genome activation.
    Akshada Shankar Ganesh, Taylor M Orban, Romir Raj, Peter I Fatzinger, Anna Johnson, Sean M Riccard, Akhmed Zhanaidarov, Mayu Inaba, Jelena Erceg.
      Chromosome territories (CTs) are intricately organized and regulated within the nucleus. Despite remarkable advances in our understanding of genome packaging and gene expression, the interplay among CTs, pairing of parental homologous chromosomes, and genome function during development remains elusive. Here, we employ an Oligopaints-based high-resolution imaging approach to examine variable CT organization in single nuclei during the developmental process of zygotic genome activation. We reveal large-scale chromosome changes with extensive homolog pairing at the whole-chromosome level that decreases locally due to spatial variability in chromosome conformations. In the absence of one homolog copy, the dynamics of CT compaction and RNA polymerase II recruitment are supported by transcriptional changes in haploid embryos. Finally, global inhibition of transcription results in decreased CT opening and no significant impact on CT pairing levels. These findings enhance our understanding of parental genome folding and regulation, which may inform strategies for chromosome-based diseases.
    DOI:  https://doi.org/10.1101/2025.04.06.647428
  13. Curr Biol. 2025 Sep 19. pii: S0960-9822(25)01118-2. [Epub ahead of print]
    A parent-of-origin effect on embryonic telomere elongation determines telomere length inheritance.
    Hyuk-Joon Jeon, Mia T Levine, Michael A Lampson.
      Telomeres are composed of specialized DNA, RNA, and proteins that interact to preserve the integrity of chromosome termini.1,2 Despite this vital function, telomere length varies dramatically within and between species. Genome-wide association studies have identified multiple genes that explain a portion of this variation,3 suggesting that telomere length is inherited as a classic quantitative trait. However, telomere length is also directly inherited as a DNA sequence. Here, we show that neither the polygenic nor the direct inheritance paradigm fully accounts for telomere length inheritance, which also depends on a parent-of-origin effect on telomere elongation in the early embryo. By reciprocally crossing mouse strains with different telomere lengths, we find that telomeres elongate in hybrid embryos only when maternal telomeres are short and paternal telomeres are long. In the reciprocal cross, telomeres shorten. These differences in embryonic telomere elongation, which emerge before zygotic genome activation, predict observed differences in adult telomere length. Moreover, when telomeres do elongate, we find molecular signatures of a recombination-based mechanism of telomere elongation, called the alternative lengthening of telomeres (ALT) pathway, previously suggested to elongate telomeres in the pre-implantation embryo. We propose that ALT is triggered by a combination of genetic asymmetry in telomere length and epigenetic asymmetry between maternal and paternal chromosomes in the zygote. Our findings offer new insight into the complex interaction of genetic and epigenetic determinants of telomere length inheritance.
    Keywords:  alternative lengthening of telomeres; pre-implantation embryo; telomere length
    DOI:  https://doi.org/10.1016/j.cub.2025.08.052
  14. Nucleic Acids Res. 2025 Sep 23. pii: gkaf945. [Epub ahead of print]53(18):
    Damage-induced phosphorylation of BRC-1/BRD-1 in meiosis preserves germline integrity.
    Nuria Fernández-Fernández, Mariola Chacón, Lola P Camino, Tatiana Garcia-Muse.
      Multiple DNA repair pathways have evolved to safeguard genome integrity and ensure organismal viability in the face of DNA damage. Errors in DNA repair processes in meiosis can lead to aneuploidy and developmental defects, but the processes that protect the germline from DNA damage remain poorly understood. Here we report a DNA damage-induced phosphorylation of the BRC-1/BRD-1 heterodimer that is essential for germline integrity in Caenorhabditis elegans. Failure to phosphorylate BRC-1/BRD-1 in response to DNA damage results in meiotic double-strand breaks (DSBs) accumulation, chromosome breakage, catastrophic diakinesis, and loss of fecundity. We further show that these defects are driven by the activity of C. elegans Bloom and Mus81, which catalyze Holliday junction dissolution and resolution, respectively. Hence, we propose that phosphorylation of BRC-1/BRD-1 in response to ionizing radiation-induced DSBs constitutes a key regulatory step that ensures the proper resolution of recombination intermediates required to preserve germline integrity.
    DOI:  https://doi.org/10.1093/nar/gkaf945
  15. Nat Commun. 2025 Sep 24. 16(1): 8357
    Three lncRNAs promote PUM protein condensation and germline differentiation.
    Roni Falk, Noa Gilad, Hanna Achache, Yisrael Rappaport, Roni Halfon, Reut Shabtai, Hasan Ishtayeh, Laura Wolovelsky, Oren Ram, Yonatan B Tzur.
      Long non-coding RNAs (lncRNAs) are abundant in gonads, yet most knockout models show no fertility defects, leaving their role unclear. Here, we identify overlapping functions of three lncRNAs in Caenorhabditis elegans fertility. These lncRNAs bind and sequester FBF-2, a regulator that inhibits germ cell differentiation. Combined deletion of the lncRNAs reduces progenitor cell number and overall progeny, reflecting additive effects. In lncRNA mutants, pro-meiotic transcripts-normally destabilized by FBF-2-are significantly reduced. FBF-2 localizes to both the cytoplasm and peri-nuclear condensates in germ cells, but its peri-nuclear condensation and association with P granules-phase-separated, evolutionarily conserved structures-are diminished in lncRNA mutants. Our findings suggest that these lncRNAs cooperatively promote fertility by spatially restricting FBF-2 within granules, thus reducing its activity and allowing the expression of differentiation-promoting transcripts. The requirement for multiple knockouts to reveal this phenotype highlights the redundancy and combinatorial function of lncRNAs in regulating germline development.
    DOI:  https://doi.org/10.1038/s41467-025-61652-x
  16. J Assist Reprod Genet. 2025 Sep 26.
    Dynamics of YAP localization and transcript activity in human oocytes and granulosa cells across early-stage folliculogenesis: an exploratory investigation.
    Jordan H Machlin, Kate Potocsky, Robin E Kruger, Jason Spence, Vasantha Padmanabhan, Ariella Shikanov.
       PURPOSE: The transcription factor yes-associated protein (YAP) has been implicated in the regulation of murine follicle activation at the level of granulosa cells (GCs); however, less is known about its role in human folliculogenesis. This study aimed to explore the localization dynamics of YAP in the nucleus and cytoplasm of oocytes and granulosa cells in human ovarian follicles.
    METHODS: YAP nuclear localization and mRNA expression of its gene target, connective tissue growth factor (CCN2), were investigated in oocytes and GCs across primordial, transitioning primordial, primary, and secondary follicles in human ovarian cortical tissue cultured up to 48 h. Slow-frozen and thawed human ovarian cortex squares (10 × 10 × 1 mm) were cut into smaller tissue strips (1 × 5 × 1 mm), and these strips were either fixed immediately (Timepoint 0) or cultured for 6, 24, or 48 h (n = 3 per timepoint). We analyzed oocytes and GCs from a total of 562 human follicles-112 primordial, 373 transitioning primordial, 65 primary, and 12 secondary.
    RESULTS: Within each timepoint, YAP nuclear localization in GCs showed significantly greater abundance at the primary stages compared to the primordial stages but remained unchanged in oocytes. Furthermore, CCN2 mRNA expression in GCs increased significantly between the primordial and secondary stages of folliculogenesis, indicating YAP is transcriptionally active in granulosa cells of growing follicles.
    CONCLUSION: Our findings provide the important insight that YAP activity in granulosa cells could be a key regulator within human follicles transitioning from primordial to primary stages, a role that is likely conserved between humans and mice.
    Keywords:  CCN2; Follicle activation; Human ovarian cortex tissue; YAP
    DOI:  https://doi.org/10.1007/s10815-025-03668-2
  17. Curr Biol. 2025 Sep 22. pii: S0960-9822(25)01085-1. [Epub ahead of print]35(18): 4537-4552.e6
    Crossover designation recruits condensin to reorganize the meiotic chromosome axis.
    Victor A Leon, Tovah E Markowitz, Soogil Hong, Adhithi R Raghavan, Jonna Heldrich, Keun P Kim, Andreas Hochwagen.
      Crossover recombination supports meiotic chromosome inheritance and fertility by establishing chiasmata between homologous chromosomes prior to the first meiotic division. In addition to the physical exchange of DNA mediated by meiotic recombination, chiasma formation also involves restructuring of the underlying chromosome axis, possibly to help with chiasma maturation or to resolve chromosomal interlocks. Here, we identify condensin as an important regulator of axis remodeling in S. cerevisiae. Condensin is recruited near sites of meiotic crossover designation by pro-crossover factors but is largely dispensable for DNA exchange. Instead, condensin helps to create discontinuities in the meiotic chromosome axis by promoting removal of cohesin. In addition, chromosomes of condensin mutants exhibit unusually common parallel chromatin clouds and experience a chromosomal buildup of the conserved axis remodeler Pch2. Consistent with an important role of axis restructuring at crossover sites, the canonical anaphase-bridge phenotype of condensin mutants is partly rescued by redirecting meiotic DNA repair to sister chromatids instead of homologous chromosomes, suggesting that crossover-associated axis reorganization is important for faithful meiotic chromosome segregation.
    Keywords:  Pch2; Rec8; Red1; ZMM factors; axial element; synapsis
    DOI:  https://doi.org/10.1016/j.cub.2025.08.019
  18. Proc Natl Acad Sci U S A. 2025 Sep 30. 122(39): e2506417122
    Sperm meet the elevated energy demands to attain fertilization competence by increasing flux through aldolase.
    Sara Violante, Aye Kyaw, Lana Kouatli, Kaushik Paladugu, Lauren Apostolakis, Macy Jenks, Amy Johnson, Ryan D Sheldon, Douglas Whitten, Anthony L Schilmiller, Pablo E Visconti, Justin R Cross, Lonny R Levin, Jochen Buck, Melanie Balbach.
      Prior to ejaculation, mammalian sperm are stored in the epididymis in a "resting" metabolic state. Upon ejaculation, sperm must alter their metabolism to generate the energy needed to support the motility and maturation process known as capacitation to reach and fertilize the oocyte. How sperm regulate the capacitation-induced increase in carbon flux is unknown. Here, we use 13C stable isotope labeling in mouse sperm isolated from the cauda epididymis to follow glucose metabolism through central carbon metabolic network before and after sperm activation. As sperm transition from resting to highly activated states, they boost energy yield by increasing flux through glycolysis at the expense of the pentose phosphate pathway. Increased glycolytic activity seems to be achieved via capacitation-induced stimulation of flux through aldolase. In the mitochondria-containing midpiece, glycolytically generated pyruvate feeds the tricarboxylic acid (TCA) cycle to further maximize energy yield via oxidative phosphorylation. In the mitochondria-free principal piece of the flagellum, pyruvate produced from glycolysis is reduced to lactate by lactate dehydrogenase, which also serves to regenerate oxidized nicotinamide adenine dinucleotide (NAD+) ensuring a sufficient supply to support glycolysis. The resultant lactate is at least partially secreted. Finally, we find evidence that there is an as yet unknown endogenous source of energy in sperm, feeding the upregulation of TCA cycle intermediates. These studies provide the most complete picture of the metabolic shift which occurs in capacitating mouse sperm in glucose.
    Keywords:  aldolase; glycolysis; metabolic reprogramming; sperm; stable isotope labeling
    DOI:  https://doi.org/10.1073/pnas.2506417122
  19. Ageing Res Rev. 2025 Sep 23. pii: S1568-1637(25)00247-8. [Epub ahead of print] 102901
    Biomarkers of female reproductive aging in gerotherapeutic clinical trials.
    Paula Benny, Ajla Hodzic Kuerec, Jessica Yu, Jovin Lee, Qian Yang, Andrea Britta Maier, Zhongwei Huang.
      The United Nations World Population Statistics reported that 10% of the global population, approximately 830 million people, were aged 65 years and older in 2024. This number is projected to double, reaching almost 20% or 1.7 billion, by 2050. With a growing aging population world-wide, age-associated diseases are also expected to increase, which has prompted research into geroscience to optimize the healthspan of aging individuals. For women, menopause significantly increases the risks of ageassociated diseases, which highlights the importance of sex-specific approaches to precision geromedicine. At present, there is a limited understanding of biomarkers of female reproductive aging and its inclusion into gerotherapeutic clinical trials. Previous gerotherapeutic trials have not specifically evaluated reproductive aging, instead focusing primarily on cardiometabolic, neurocognitive, and musculoskeletal outcomes. In contrast, clinical studies targeting subfertility often assess biomarkers such as AMH, FSH, and LH, while trials addressing menopausal symptoms commonly apply the STRAW+10 criteria for reproductive staging. Only recently has ovarian aging been recognized as a critical determinant of women's overall health, extending beyond its role in fertility. Therefore, this article discusses the available (FSH, AMH, Inhibin, antral follicle count) as well as the emerging biomarkers (estradiol, progesterone, LH, Sirtuin- 1, microRNAs, menstrual blood markers, epigenetic markers, ovarian stiffness, vaginal microbiome markers, survey information) of female reproductive aging and a protocol for evaluating the impact of gerotherapeutics in clinical trials. Using an example of a Phase 2 Clinical Trial (1 year), short-term (every 3 months) and long-term (every 6 months) follow-ups can be performed. Importantly, female reproductive lifestage should be taken into consideration when prescribing gerotherapeutics to improve female reproductive aging, ultimately optimizing the health and healthspan of females.
    Keywords:  biomarkers; clinical trials, gerotherapeutics; female reproductive aging; menopause
    DOI:  https://doi.org/10.1016/j.arr.2025.102901
  20. Endocrinology. 2025 Sep 24. pii: bqaf142. [Epub ahead of print]
    Loss of inhibin negative feedback to pituitary gonadotropes leads to enhanced ovulation but pregnancy failure in mice.
    Yeu-Farn Lin, Emilie Brûlé, Luisina Ongaro, Xiang Zhou, Yangfan Jin, Hailey Schultz, Mitra Cowan, David G Stouffer, Ali Yaman, Richard J Auchus, Ulrich Boehm, Daniel J Bernard.
      Follicle-stimulating hormone (FSH) is an essential regulator of ovarian function. Inhibins are TGFβ family ligands produced in the gonads that suppress FSH synthesis by pituitary gonadotrope cells. Inhibins require a co-receptor, betaglycan or TGFBR3L, to mediate their actions. Female mice with a gonadotrope-specific knockout of betaglycan or global deletion of Tgfbr3l have increased FSH activity or levels and produce larger litters compared to controls. Females with both co-receptors knocked out (hereafter dKO) have dramatically increased circulating FSH, ovulate about 4 times as many eggs in natural cycles as controls but are infertile. Here, we show that dKO females show an increased number of implanted embryos at 7.5 days post coitum (dpc) but that their pregnancies fail around mid-gestation. Wild-type surrogates give birth to live young following transplantation of embryos from control or dKO females. Conversely, control but not dKO females can carry wild-type embryos to term, suggesting that the maternal environment in dKO mice cannot support full term pregnancies. Elevated estradiol levels are deleterious to pregnancy in mice, and we detected increased estradiol production in ovaries of pregnant dKOs. Treatment of these animals with aromatase inhibitors or a selective estrogen receptor degrader increased fetal survival. The results indicate that loss of inhibin action in murine gonadotropes results in excess estradiol during pregnancy that precludes successful pregnancy.
    Keywords:  FSH; folliculogenesis; infertility; inhibin; pituitary
    DOI:  https://doi.org/10.1210/endocr/bqaf142
  21. Cell Genom. 2025 Sep 25. pii: S2666-979X(25)00268-X. [Epub ahead of print] 101012
    Genetic landscape of human oocyte/embryo defects.
    Biaobang Chen, Weijie Wang, Juanzi Shi, Xiaoxi Sun, Yichun Guan, Guimin Hao, Junli Zhao, Jian Mu, Zhihua Zhang, Fangzhou Xu, Dengying Gao, Zhiqi Pan, Ran Yu, Hao Gu, Huizhen Fan, Yuxi Luo, Siyuan Xie, Xingzhu Du, Huixia Jing, Zhiqi Ye, Xuelin Zhang, Ruiqi Hai, Hongying Zhu, Tianyu Wu, Qiaoli Li, Jing Fu, Ling Wu, Wenjing Wang, Chunyi Li, Feiyang Diao, Qiuwen Shi, Lin Li, Shiru Xu, Da Li, Xi Dong, Peng Xu, Jiucun Wang, Lin He, Yanping Kuang, Qing Sang, Lei Wang.
      Oocyte/embryo defects can result in oocyte maturation arrest, fertilization failure, embryonic arrest, and infertility as well as recurrent in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) failures. However, the genetic determinants of human oocyte/embryo defects remain largely unknown, and the overall genetic diagnostic yield for such defects has not been evaluated. Here, we performed exome sequencing in 3,627 patients with oocyte/embryo defects. We identified a total of 479 positive cases carrying variants in 37 known genes, indicating a diagnostic yield of 13.2%. Case-control association studies combined with gene set enrichment analysis identified 123 novel candidate genes responsible for oocyte/embryo defects. These results provide a comprehensive genetic landscape of human oocyte/embryo defects and highlight the clinical significance of genetic counseling in infertile patients with oocyte/embryo defects. Our study will lay the foundation for transforming the traditional clinical practice for failed IVF/ICSI attempts into genetic-based precision and personalized treatment for these patients.
    Keywords:  exome sequencing; female infertility; genetic mutations; oocyte/embryo defects
    DOI:  https://doi.org/10.1016/j.xgen.2025.101012
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