bims-cebooc Biomed News
on Cell biology of oocytes
Issue of 2025–08–17
twenty papers selected by
Gabriele Zaffagnini, Universität zu Köln
  1. Protein Storage in Oocytes: Implications for Oocyte Quality, Embryonic Development, and Female Fertility.
  2. Establishment of chromatin architecture interplays with embryo hypertranscription.
  3. Maternal/zygotic knockout and ddPCR analysis question the role of activin A in preimplantation mouse embryo development†.
  4. Building bridges for oocyte growth: regulation of C. elegans germline architecture and function by oriented cell divisions.
  5. Mechanisms underlying low mutation rates in mammalian oocytes and preimplantation embryos.
  6. Nuclear Hormone Receptor NHR-49/HNF4α Couples Fertility Regulation to Resource Allocation and Longevity in C. elegans.
  7. UHRF2 mediates resistance to DNA methylation reprogramming in primordial germ cells.
  8. KDM5B impairs oocyte quality and causes embryo arrest via epigenetic regulation of spindle assembly and chromosome arrangement.
  9. Transcription factor-mediated germ cell induction in rats reveals ETV4 cooperates with germline specifiers.
  10. Nuclear Envelope Membrane Protein 1 plays crucial and conserved roles in female meiosis.
  11. Initiation of meiosis from human iPSCs under defined conditions through identification of regulatory factors.
  12. Redistribution of fragmented mitochondria ensures symmetric organelle partitioning and faithful chromosome segregation in mitotic mouse zygotes.
  13. The timing of maternal protein degradation during mammalian preimplantation development is species-specific.
  14. Rab10 regulates cortical granule translocation and ZP2 dynamics for zona pellucida function during oocyte maturation.
  15. Biallelic variants in DLGAP5 cause spindle assembly defects and human early embryonic arrest.
  16. Capturing ovarian dynamics through spatial profiling of the mechano-microenvironment.
  17. Resolving early embryonic metabolism in Drosophila through single-embryo metabolomics and transcriptomics.
  18. Hexokinase regulates Mondo-mediated longevity via the PPP and organellar dynamics.
  19. TOR signalling mediates the collective movement of Border cells in Drosophila oogenesis.
  20. Psrc1 Ensures Proper Spindle Assembly and Chromosome Segregation During Mouse Oocyte Maturation.
  1. Annu Rev Cell Dev Biol. 2025 Aug 13.
    Protein Storage in Oocytes: Implications for Oocyte Quality, Embryonic Development, and Female Fertility.
    Ida Marie Astad Jentoft, Melina Schuh.
      Maternal storage is a fundamental feature of female gametes and is essential for maintaining oocyte quality and preserving developmental competence. Embryonic development relies on maternally deposited proteins, transcripts, and nutrients, yet the mechanisms by which oocytes accumulate and store these critical factors-particularly proteins-remain poorly understood. Across eukaryotes, diverse protein storage strategies have evolved, reflecting both conserved and species-specific adaptations. Here, we review the mechanisms of oocyte protein storage, comparing different species to uncover functional similarities and differences. Additionally, germ cells must clear damaged molecules accumulated during the mother's lifetime to ensure the production of rejuvenated eggs. We examine the conserved proteostasis mechanisms that support this process. By integrating insights from various model organisms and cellular dormancy studies, this review highlights the molecular basis of oocyte protein storage and its vital role in reproductive success.
    DOI:  https://doi.org/10.1146/annurev-cellbio-101323-031045
  2. Nature. 2025 Aug 13.
    Establishment of chromatin architecture interplays with embryo hypertranscription.
    Guang Yu, Kai Xu, Weikun Xia, Ke Zhang, Qianhua Xu, Lijia Li, Zili Lin, Ling Liu, Bofeng Liu, Zhenhai Du, Xia Chen, Qiang Fan, Fangnong Lai, Wenying Wang, Lijuan Wang, Feng Kong, Chao Wang, Haiqiang Dai, Huili Wang, Wei Xie.
      After fertilization, early embryos undergo dissolution of conventional chromatin organization, including topologically associating domains (TADs)1,2. Zygotic genome activation then commences amid unusually slow de novo establishment of three-dimensional chromatin architecture2. How chromatin organization is established and how it interplays with transcription in early mammalian embryos remain elusive. Here we show that CTCF occupies chromatin throughout mouse early development. By contrast, cohesin poorly binds chromatin in one-cell embryos, coinciding with TAD dissolution. Cohesin binding then progressively increases from two- to eight-cell embryos, accompanying TAD establishment. Unexpectedly, strong 'genic cohesin islands' (GCIs) emerge across gene bodies of active genes in this period. GCI genes enrich for cell identity and regulatory genes, display broad H3K4me3 at promoters, and exhibit strong binding of transcription factors and the cohesin loader NIPBL at nearby enhancers. We show that transcription is hyperactive in two- to eight-cell embryos and is required for GCI formation. Conversely, induced transcription can also create GCIs. Finally, GCIs can function as insulation boundaries and form contact domains with nearby CTCF sites, enhancing both the transcription levels and stability of GCI genes. These data reveal a hypertranscription state in early embryos that both shapes and is fostered by the three-dimensional genome organization, revealing an intimate interplay between chromatin structure and transcription.
    DOI:  https://doi.org/10.1038/s41586-025-09400-5
  3. Biol Reprod. 2025 Aug 15. pii: ioaf189. [Epub ahead of print]
    Maternal/zygotic knockout and ddPCR analysis question the role of activin A in preimplantation mouse embryo development†.
    Eliza Winek, Katarzyna Szczepańska, Lidia Wolińska-Nizioł, Katarzyna Zgódka, Michaela Vaskovicova, David Drutovic, Aneta Suwińska.
      For many years, activin A, encoded by Inhba, has been thought to be present in both mouse and human oocytes and preimplantation embryos. However, its deficiency does not impede the proper embryonic development of the embryo until birth. It has been suggested that the lack of a phenotype in zygotic knockout embryos may be masked by the presence of maternal protein deposited in the oocyte during oogenesis or provided from the reproductive tract. Therefore, to explore whether maternally supplied activin A is required for embryo development, we carried out a conditional Inhba knockout in oocytes using Zp3-Cre/LoxP strategy. By examining Inhba maternal and maternal/zygotic knockout embryos, individually recorded using time-lapse imaging, immunostained, and genotyped, we revealed that the maternal pool of activin A affects the dynamics of mouse preimplantation development. These alterations are accompanied by impaired mitochondrial activity in oocytes. Surprisingly, using the droplet digital polymerase chain reaction (ddPCR) approach, we provided evidence that the Inhba mRNA of zygotic origin is undetectable in mouse embryos.
    Keywords:  Activin a; Ddpcr; Inhba; Maternal knockout; Preimplantation embryo
    DOI:  https://doi.org/10.1093/biolre/ioaf189
  4. Dev Biol. 2025 Aug 08. pii: S0012-1606(25)00222-2. [Epub ahead of print]527 91-96
    Building bridges for oocyte growth: regulation of C. elegans germline architecture and function by oriented cell divisions.
    Réda M Zellag, Kimia Zarnani, Abigail R Gerhold, Jean-Claude Labbé.
      In most animals, the growth of oocytes depends on the delivery of cytoplasm from other germ cells ("nurse" cells) via cytoplasmic bridges. In some cases, such as in mice and Drosophila, these bridges are formed via incomplete cytokinesis and connect the germ cells to the oocyte directly. In other animals, like the nematode Caenorhabditis elegans (C. elegans), germ cells are connected to an anucleate core of cytoplasm, termed the rachis, that supplies materials to the oocyte. This difference in germline architecture poses an interesting challenge for tissue development. Whereas in the first case, stabilization of the cytokinetic ring between dividing germ cells produces the final organization, with the total number of cytoplasmic bridges being one fewer than the total number of germ cells; in the second scenario, germ cell division must produce two daughter cells each with their own connection to the rachis, with the total number of cytoplasmic bridges being equal to the number of germ cells. The cellular and molecular mechanisms that enable germ cells to form and maintain this latter type of architecture are incompletely understood but have been under increasing scrutiny over the last years. Here we review the recent progress in understanding C. elegans germline development from a tissue architecture perspective.
    Keywords:  Germ cell cytokinesis; Germline development and organization; Germline syncytium regulation; Mitotic spindle orientation; Stable cytoplasmic bridges
    DOI:  https://doi.org/10.1016/j.ydbio.2025.08.005
  5. Nucleic Acids Res. 2025 Aug 11. pii: gkaf760. [Epub ahead of print]53(15):
    Mechanisms underlying low mutation rates in mammalian oocytes and preimplantation embryos.
    Nataliia Dudko, Jurek W Dobrucki, Helena Fulka.
      Mammalian oocytes and embryos are known to exhibit a markedly low frequency of de novo mutations compared to somatic cells. We still lack efficient tools to carry out functional studies of the intergenerational mechanism of genome protection, and our view of this phenomenon is constantly being modified in light of the new results. Although oocytes were originally considered a cell type lacking DNA repair, new results indicate that mammalian oocytes might possess a set of unique properties that make them and their descendants resistant to accumulation of DNA damage. Here, we review various factors that can influence oocyte and embryo genome stability and discuss the functional evidence for the uniquely efficient response to DNA damage, particularly in the presence of minor DNA lesions and single-strand breaks. We discuss whether high levels of DNA repair proteins might be the basis for the observed low mutation rate. Finally, we present the idea that the unique characteristics of the chromatin landscape, as well as the limited replication, rather than the abundance of repair factors alone, may be responsible for the intergenerational protection of the genome.
    DOI:  https://doi.org/10.1093/nar/gkaf760
  6. bioRxiv. 2025 Jul 18. pii: 2025.07.14.664468. [Epub ahead of print]
    Nuclear Hormone Receptor NHR-49/HNF4α Couples Fertility Regulation to Resource Allocation and Longevity in C. elegans.
    Sharada Gopal, Amaresh Chaturbedi, Tej Ramachandrula, John OuYang, Rebecca Rodell, Siu Sylvia Lee.
      The nuclear hormone receptor NHR-49, a homolog of mammalian PPARα and HNF4α, is a key transcriptional regulator of nutrition sensing and fatty acid metabolism in Caenorhabditis elegans . Here we uncovered a new function of NHR-49 in reproduction - controlling oocyte activation and ovulation. Loss of NHR-49 causes inappropriate oocyte activation and laying of unfertilized oocytes in the absence of sperm, resulting in rapid loss of yolk and stored fat, and drastically shortening of lifespan. We further demonstrated that prevention of yolk transfer into the oocytes largely restore fat storage and partially rescue lifespan in the nhr-49 mutants. Additionally, NHR-49 appears to couple germline proliferation to nutritional status, as evidenced by its requirement for starvation-induced reduction in germline proliferation. Mechanistically, we showed that NHR-49 primarily acts in somatic cells, rather than the germline itself, to regulate oocyte activation and ovulation. We further demonstrated that NHR-49 binds to the promoter of GSA-1 and may stimulate its expression. GSA-1 encodes a G-protein coupled receptor known to act in the gonadal sheath cells to couple sperm sensing and oocyte activation. Our findings therefore suggest a model whereby NHR-49 regulates the expression of GSA-1, which in turn regulates oocyte activation in response to sperm signal. Overall, our findings suggest a mechanistic link between nutrition sensing and fertility and point to regulated retention of reproductive resources to be critical for maintaining longevity.
    Highlights: A new role of NHR-49 in regulating oocyte activation and ovulation Inappropriate laying of unfertilized oocytes contributes to the fat loss and lifespan shortening of nhr-49 mutants NHR-49 acts from somatic cells, not germline, to restrain oocyte activation NHR-49 binds to the promoter of GSA-1 and likely represses gsa-1 expression to regulate oocyte activation.
    Abstract Figure:
    DOI:  https://doi.org/10.1101/2025.07.14.664468
  7. Nat Commun. 2025 Aug 09. 16(1): 7350
    UHRF2 mediates resistance to DNA methylation reprogramming in primordial germ cells.
    Ambre Bender, Marion Morel, Michael Dumas, Muriel Klopfenstein, Naël Osmani, Maxim V C Greenberg, Déborah Bourc'his, Norbert B Ghyselinck, Michael Weber.
      In mammals, primordial germ cells (PGCs) undergo global erasure of DNA methylation with delayed demethylation of germline genes and selective retention of DNA methylation at evolutionarily young retrotransposons. However, the molecular mechanisms of persistent DNA methylation in PGCs remain unclear. Here we report that resistance to DNA methylation reprogramming in PGCs requires UHRF2, the paralog of the DNMT1 cofactor UHRF1. PGCs from Uhrf2 knock-out mice show loss of retrotransposon DNA methylation, while DNA methylation is unaffected in somatic cells. This is not associated with changes in the expression of retrotransposons in E13.5 PGCs, indicating that other mechanisms compensate for retrotransposon control at this stage. Furthermore, Uhrf2-deficient PGCs show precocious demethylation of germline genes and overexpress meiotic genes in females. Subsequently, Uhrf2-deficient mice show impaired oocyte development and female-specific reduced fertility, as well as incomplete remethylation of retrotransposons during spermatogenesis. These findings reveal a crucial function for the UHRF1 paralog UHRF2 in controlling DNA methylation in the germline.
    DOI:  https://doi.org/10.1038/s41467-025-61954-0
  8. Theriogenology. 2025 Aug 09. pii: S0093-691X(25)00357-7. [Epub ahead of print]249 117631
    KDM5B impairs oocyte quality and causes embryo arrest via epigenetic regulation of spindle assembly and chromosome arrangement.
    Yingnan Yang, Xiaowei Chen, Mingtian Deng, Feng Wang.
      Oocyte-stored maternal factors are critical for successful embryonic development, but they are remained incompletely understood. Histone demethylase KDM5B has been implicated in the regulation of embryonic development and genomic stability. However, the specific role of KDM5B during oocyte maturation and early embryogenesis remains unclear in goat. In this study, we investigated the function of KDM5B during goat oocyte maturation and early embryogenesis. Using GSK467, a selective KDM5B inhibitor, we observed increased H3K4me3 accumulation in both oocytes and parthenogenetically activated (PA) embryos. Secondly, inhibition of KDM5B disrupted spindle assembly and chromosome alignment, induced DNA damage, and significantly reduced the oocyte maturation rate in both goat and mouse models. Moreover, inhibition of KDM5B leads to developmental arrest of PA embryos, and low-input RNA sequencing of 8-cell-stage PA embryos revealed defective maternal mRNA degradation and impaired zygotic genome activation. In summary, our findings demonstrate that KDM5B plays a critical role in regulating spindle assembly and chromosome alignment maintaining oocyte quality, and supporting early embryo development. This study provides new insights into the epigenetic regulation of reproductive competence in mammals.
    Keywords:  Chromosome arrangement; KDM5B; Oocyte maturation; Spindle assembly; Zygotic gene
    DOI:  https://doi.org/10.1016/j.theriogenology.2025.117631
  9. Stem Cell Reports. 2025 Aug 12. pii: S2213-6711(25)00203-6. [Epub ahead of print]20(8): 102599
    Transcription factor-mediated germ cell induction in rats reveals ETV4 cooperates with germline specifiers.
    Mami Oikawa, Hiroki Kojima, Hisato Kobayashi, Kenyu Iwatsuki, Hijiri Saito, Makoto Sanbo, Kazumi Nishioka, Tomoyuki Yamaguchi, Takuya Yamamoto, Kazuki Kurimoto, Masumi Hirabayashi, Toshihiro Kobayashi.
      The specification of primordial germ cells (PGCs) marks a crucial branchpoint in early embryonic development. Studying the molecular mechanisms governing this process is crucial for understanding reproduction and evolution. Here, we identify transcription factors essential for PGC specification in rats using an in vitro system to induce PGC-like cells (PGCLCs) from pluripotent cells. Overexpression of Tbxt, a key mesodermal factor activating the germ cell program in epiblast-like cells, induces functional rat PGCLCs, similar to mice. However, unlike in mice, overexpression of the PGC specifiers (Prdm14, Blimp1, and Ap2γ) alone is not sufficient in rats; additional Activin and WNT signals are necessary for PGCLC induction. Through a candidate screen, we identified the transcription factor Etv4 acting cooperatively with the three PGC specifiers. Our study provides insight into the mechanism behind germline segregation in mammals and underscores the importance of using the rat model in addition to mice.
    Keywords:  pluripotent stem cell; primordial germ cell; rat
    DOI:  https://doi.org/10.1016/j.stemcr.2025.102599
  10. Res Sq. 2025 Aug 04. pii: rs.3.rs-7159889. [Epub ahead of print]
    Nuclear Envelope Membrane Protein 1 plays crucial and conserved roles in female meiosis.
    Helen McNeill, Bilal Hakim, Yonit Tsatskis, Ling Zhang, Esther Choi, Ying Zhang, Didier Hodzic, Que Wu, MuYun Zhang, Maryam Pashaei, Kyungwon Ha, Julie Brill, Miguel Brieño-Enríquez, Andrea Jurisicova.
      Female germ cells must preserve the integrity of their genome and generate genetic diversity via meiotic recombination. This challenging process, which occurs during fetal life, 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 inner nuclear membrane proteins which are critical for fertility in flies, worms, fish and mice, and mechanically support the nuclear envelope. However, why NEMP homologs are required for fertility is still unclear. Using both Drosophila and mouse models, we establish here that loss of Nemp1 leads to activation of an ATM-CHK2 DNA damage pathway and results in massive loss of oocytes during fetal life. Chemical or genetic inactivation of the ATM-CHK2-p63 pathway reduces oocyte loss, demonstrating its importance upon loss of Nemp1. 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 for timely and precise execution of meiotic prophase and is crucial for accurate pairing and synapsis, oocyte developmental competence and survival.
    DOI:  https://doi.org/10.21203/rs.3.rs-7159889/v1
  11. Sci Adv. 2025 Aug 15. 11(33): eadu0384
    Initiation of meiosis from human iPSCs under defined conditions through identification of regulatory factors.
    Merrick Pierson Smela, Jessica Adams, Carl Ma, Laura Breimann, Ursula Widocki, Bogdan Dobre, Toshihiro Shioda, George M Church.
      Meiotic failure is a major cause of infertility, but the lack of an in vitro model of human meiosis is a barrier to understanding its mechanism. Here, we establish a method to initiate meiosis directly from male or female human-induced pluripotent stem cells (iPSCs). DNMT1 inhibition, retinoid signaling activation, and overexpression of regulatory factors (antiapoptotic BCL2 and promeiotic HOXB5, BOLL, or MEIOC) rapidly activates meiosis over a 15-day protocol. Our protocol bypasses the primordial germ cell stage and directly generates cells expressing genes similar to meiotic oogonia, including oogonia markers, all synaptonemal complex components, and meiotic recombination machinery. DNMT1 inhibition rapidly erases DNA methylation, including at imprinting control regions and promoters of meiotic genes. Microscopy shows key aspects of meiosis, including chromosome axis formation and synapsis in live human cells. Our model of human meiosis provides opportunities for studying this critical reproductive process under chemically defined conditions in vitro.
    DOI:  https://doi.org/10.1126/sciadv.adu0384
  12. Elife. 2025 Aug 11. pii: RP99936. [Epub ahead of print]13
    Redistribution of fragmented mitochondria ensures symmetric organelle partitioning and faithful chromosome segregation in mitotic mouse zygotes.
    Haruna Gekko, Ruri Nomura, Daiki Kuzuhara, Masato Kaneyasu, Genpei Koseki, Deepak Adhikari, Yasuyuki Mio, John Carroll, Tomohiro Kono, Hiroaki Funahashi, Takuya Wakai.
      In cleavage-stage embryos, preexisting organelles partition evenly into daughter blastomeres without significant cell growth after symmetric cell division. The presence of mitochondrial DNA within mitochondria and its restricted replication during preimplantation development makes their inheritance particularly important. While chromosomes are precisely segregated by the mitotic spindle, the mechanisms controlling mitochondrial partitioning remain poorly understood. In this study, we investigate the mechanism by which Dynamin-related protein 1 (Drp1) controls the mitochondrial redistribution and partitioning during embryonic cleavage. Depletion of Drp1 in mouse zygotes causes marked mitochondrial aggregation, and the majority of embryos arrest at the 2 cell stage. Clumped mitochondria are located in the center of mitotic Drp1-depleted zygotes with less uniform distribution, thereby preventing their symmetric partitioning. Asymmetric mitochondrial inheritance is accompanied by functionally inequivalent blastomeres with biased ATP and endoplasmic reticulum Ca2+ levels. We also find that marked mitochondrial centration in Drp1-depleted zygotes prevents the assembly of parental chromosomes, resulting in chromosome segregation defects and binucleation. Thus, mitochondrial fragmentation mediated by Drp1 ensures proper organelle positioning and partitioning into functional daughters during the first embryonic cleavage.
    Keywords:  Dynamin-related protein 1; binuclear formation; chromosome segregation; developmental biology; mitochondrial dynamics; mouse; organelle inheritance; preimplantation development
    DOI:  https://doi.org/10.7554/eLife.99936
  13. Reproduction. 2025 Sep 01. pii: e250007. [Epub ahead of print]170(3):
    The timing of maternal protein degradation during mammalian preimplantation development is species-specific.
    Veronika Kinterova, Alexandra Rosenbaum Bartkova, Shanjida Afrin, Jiri Kanka, Andrej Susor, Radek Prochazka, Tereza Toralova.
       In brief: Proper degradation of maternally inherited proteins is a prerequisite for successful embryonic development. This study shows the species-specificity of this process.
    Abstract: The mechanism of targeting maternal proteins for degradation during preimplantation development is an unexplored process. Only a few proteins that need to be degraded for the proper course of the maternal-to-zygotic transition have been described in mice, and a few more in non-mammalian species. However, it is not well known whether the need for degradation is conserved across species or if it is driven in a species-specific way. Therefore, we selected six proteins that need to be degraded for the proper course of the maternal-to-zygotic transition in mice or Xenopus, and thoroughly characterized their expression at both the mRNA and protein level during bovine embryogenesis. Further, we analysed the protein expression in mice and pigs and compared it to bovine embryos. Thus, we provide a unique interspecies comparison of three mammalian representatives. We found that the degree of conservation between species is low and does not depend on the evolutionary relatedness of the species. This paper suggests that protein degradation during preimplantation development is controlled by a combination of species-specific factors from the embryo and the sequences of protein homologues.
    Keywords:  cattle; embryonic genome activation; maternal protein; preimplantation development; protein degradation
    DOI:  https://doi.org/10.1530/REP-25-0007
  14. Development. 2025 Aug 11. pii: dev.204665. [Epub ahead of print]
    Rab10 regulates cortical granule translocation and ZP2 dynamics for zona pellucida function during oocyte maturation.
    Hong-Hui Wang, Kun-Huan Zhang, Si-Le Wu, Meng-Hao Pan, Xiao-Han Li, Shao-Chen Sun.
      Successful fertilization is important for early embryo development and offspring generation. Cortical granules which are formed in the cytoplasm, are transported to the cortex to avoid polyspermy which prevent sperm penetration into oocytes. The underlying mechanism is still largely unknown. In present study, we identified that GTPase Rab10-mediated vesicles played a pivotal role on actin dynamics, which regulated cortical granule transport and ZP2 function in mouse and porcine oocytes. We found that Rab10 accumulated at the oocyte cortex and modulated RhoA pathway to control actin dynamics, and disrupting the functions of Rab10 affected myosin Va expression, which impaired cortical granule movement to the cortex, causing insufficient supply of cortical granules contents and weakened zona pellucida modification. Besides, overexpression of GDP-bound Rab10 led to ZP2 down-regulation and accumulation at the cortex, which affected zona pellucida reaction. Taken together, our findings demonstrated that Rab10 regulated RhoA pathway for actin dynamics and myosin Va complex for cortical granule-based cortical reaction, and Rab10-ZP2 complex contributes to ZP2 supply for zona pellucida reaction.
    Keywords:  Actin; Fertilization; Meiosis; Oocyte; Vesicle
    DOI:  https://doi.org/10.1242/dev.204665
  15. Hum Reprod. 2025 Aug 12. pii: deaf158. [Epub ahead of print]
    Biallelic variants in DLGAP5 cause spindle assembly defects and human early embryonic arrest.
    Huiling Hu, Xian Wan, Jiaqi Sun, Shen Zhang, Jing Guo, Yinli Zhang, Fei Meng, Shuoping Zhang, Yifan Gu, Fei Gong, Hongqing Liao, Ge Lin, Wei Zheng.
       STUDY QUESTION: What effects do DLGAP5 defects have on human early embryo development?
    SUMMARY ANSWER: DLGAP5 deficiency disrupts normal spindle assembly through its interaction with TACC3, leading to female infertility characterized by recurrent early embryonic arrest (REEA).
    WHAT IS KNOWN ALREADY: REEA is a significant contributor to failures in assisted reproductive technology. While genetic factors play a crucial role, known gene variants account for only a small proportion of affected individuals, leaving many underlying genetic factors yet to be elucidated. The relationship between spindle assembly and early embryonic development has emerged as a key research focus, however, our understanding of bipolar spindles in human oocytes and early embryos remains limited, highlighting the need for further investigation into the essential molecular players involved.
    STUDY DESIGN, SIZE, DURATION: A total of 488 female patients experiencing infertility characterized as REEA were recruited from a university-affiliated center from November 2021 to December 2023.
    PARTICIPANTS/MATERIALS, SETTING, METHODS: Whole-exome sequencing was performed on the REEA cohort to identify candidate variants. HeLa cells were transiently transfected with wild-type and mutant plasmids to evaluate protein abundance and localization. Mutant mRNAs were expressed at the zygote stage to monitor subsequent embryonic development. Immunoprecipitation-mass spectrometry was employed to identify altered interacting molecules associated with the candidate variants. Additionally, a site-directed mutant mouse model was developed to investigate the pathogenic mechanisms in vivo, validated with patient oocytes and arrested embryos.
    MAIN RESULTS AND THE ROLE OF CHANCE: The study identified two nonsense variants, one frameshift variant, and one missense pathogenic variant in the DLGAP5 gene of three independent families from the cohort of 488 REEA patients through whole-exome sequencing. All affected individuals displayed a Mendelian recessive inheritance pattern. These variants significantly altered protein length, abundance, or localization, resulting in spindle abnormalities in HeLa cells and mouse zygotes. Furthermore, the microinjection of exogenous mutant DLGAP5 mRNA into mouse zygote and the construction of Dlgap5 site-directed mutant mice successfully replicated the patient phenotypes. Functional studies, both in vivo and in vitro, revealed that DLGAP5 deficiency disrupts normal spindle assembly through its interaction with TACC3.
    LIMITATIONS, REASONS FOR CAUTION: This study was unable to observe the dynamic changes in spindle assembly in oocytes from patients with DLGAP5 variants due to ethical restrictions. Additionally, a larger patient cohort is needed, particularly multi-center and multi-ethnic studies, to further establish the relationship between DLGAP5 variants and female infertility.
    WIDER IMPLICATIONS OF THE FINDINGS: These findings suggest that DLGAP5 is essential for spindle assembly in oocytes through its interaction with TACC3. This could position DLGAP5 as a novel molecular diagnostic marker and a potential target for interventions in female infertility related to REEA.
    STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Natural Science Foundation of China (82371672 and 82371667), the National Key Research and Development Program of China (2023YFC2705504 and 2022YFC2702300), the Natural Science Foundation of Hunan Province (2024JJ2083), the Science and Technology Innovation Program of Hunan Province (2023RC3233) and the Scientific Research Foundation of Reproductive and Genetic Hospital of CITIC-XIANGYA (YNXM-202202 and YNXM-202402), and Hunan Provincial Grant for Innovative Province Construction (2019SK4012). The authors declare they have no conflict of interest.
    TRIAL REGISTRATION NUMBER: N/A.
    Keywords:   DLGAP5 variant; TACC3 interaction; assisted reproductive technology; early embryonic arrest; female infertility; spindle
    DOI:  https://doi.org/10.1093/humrep/deaf158
  16. Semin Cell Dev Biol. 2025 Aug 11. pii: S1084-9521(25)00052-7. [Epub ahead of print]175 103642
    Capturing ovarian dynamics through spatial profiling of the mechano-microenvironment.
    Kosei Tomida, Huan Ting Ong, Jennifer L Young, Chii Jou Chan.
      In recent years, tissue mechanics has been recognized not as a passive outcome of development but may function as upstream regulators to guide cellular functions such as proliferation, migration, and differentiation. In mammalian ovaries, cross-scale mechanical signals arising from tissue deformation, extracellular matrix architecture, and intrafollicular pressure dynamically evolve over the reproductive lifespan, contributing to a complex biomechanical landscape. Despite increasing recognition of their role in regulating follicle development, mechanical signals from ovarian microenvironment are still often considered separately from changes in gene expression and metabolic pathways. In addition, comprehensive mapping of the ovarian mechano-microenvironment remains lacking, in part due to challenges in assessing mechanical information in ovaries. Here we discuss how emerging biophysical techniques, including the latest advancement in various omics technologies, allow us to probe ovarian mechanics across multiple length scales. Such an integrated approach will provide new insights on how force transmission, matrix remodeling, and cellular signaling intersect within defined spatial niches to regulate ovarian dynamics, paving the way for future understanding of the mechanobiological basis of reproductive disorders.
    Keywords:  Biomechanics; Folliculogenesis; Mechanobiology; Oocyte; Ovary; Spatio-omics; Tissue mechanics
    DOI:  https://doi.org/10.1016/j.semcdb.2025.103642
  17. Nat Metab. 2025 Aug 13.
    Resolving early embryonic metabolism in Drosophila through single-embryo metabolomics and transcriptomics.
    J Eduardo Pérez-Mojica, Zachary B Madaj, Christine Isaguirre, Joe Roy, Kin H Lau, Ryan D Sheldon, Adelheid Lempradl.
      Early embryonic development marks a shift from maternal factor reliance to zygotic control. Although transcriptional regulation during this period is well characterized, concurrent metabolic events remain largely unknown. Progress has been limited by technical challenges in analysing the small amounts of material and the rapid progression of development. Here, we present a high-resolution, single-embryo multi-omics dataset that captures transcriptional and metabolic dynamics during the first 3 h of Drosophila development. By profiling individual embryos, we uncover stage-specific transcriptional and metabolic programmes, including previously unrecognized transitions in nucleotides, amino acids and other metabolites. Integration of metabolites and transcript modules reveals a limited, selective functional coupling between metabolism and gene expression. This work reframes the maternal-to-zygotic transition as both a transcriptional and metabolic handoff and provides a valuable framework for studying metabolic regulation during development and beyond.
    DOI:  https://doi.org/10.1038/s42255-025-01351-5
  18. Elife. 2025 Aug 11. pii: RP89225. [Epub ahead of print]12
    Hexokinase regulates Mondo-mediated longevity via the PPP and organellar dynamics.
    Raymond Laboy, Marjana Ndoci, Shamsh Tabrez Syed, Maximilian Vonolfen, Eugen Ballhysa, Tim Droth, Klara Schilling, Anna Loehrke, Ilian Atanassov, Adam Antebi.
      The transcriptional complex Mondo/Max-like, MML-1/MXL-2, acts as a convergent transcriptional regulatory output of multiple longevity pathways in Caenorhabditis elegans. These transcription factors coordinate nutrient sensing with carbohydrate and lipid metabolism across the evolutionary spectrum. While most studies have focused on the downstream outputs, little is known about the upstream inputs that regulate these transcription factors in a live organism. Here, we found that knockdown of various glucose metabolic enzymes decreases MML-1 localization in the nucleus and identified two hexokinase isozymes, hxk-1 and hxk-2, as the most vigorous regulators of MML-1 function. Upon hexokinase knockdown, MML-1 redistributes to mitochondria and lipid droplets (LDs), and concomitantly, transcriptional targets are downregulated and germline longevity is abolished. Further, we found that hxk-1 regulates MML-1 through mitochondrial β-oxidation, while hxk-2 regulates MML-1 by modulating the pentose phosphate pathway (PPP) and its coordinated association with LDs. Similarly, inhibition of the PPP rescues mammalian MondoA nuclear translocation and transcriptional function upon starvation. These studies reveal how metabolic signals and organellar communication regulate a key convergent metabolic transcription factor to promote longevity.
    Keywords:  C. elegans; MML-1; MondoA; cell biology; hexokinase; human; longevity; metabolism
    DOI:  https://doi.org/10.7554/eLife.89225
  19. Development. 2025 Aug 11. pii: dev.204612. [Epub ahead of print]
    TOR signalling mediates the collective movement of Border cells in Drosophila oogenesis.
    Sudipta Halder, Adhisree Sharma, Sayan Acharjee, Neha Biju, Mincy Kunjumon, Rohan Jayant Khadilkar, Mohit Prasad.
      Collective cell migration is seen in various biological processes spanning embryonic development, organogenesis, wound healing and, unfortunately, cancer metastasis. Here, we have examined the role of the evolutionary conserved Target of Rapamycin signalling (TOR) in mediating collective cell movement employing the model of migrating BCs in Drosophila oogenesis. Though TOR signalling is classically linked to cell growth, cell proliferation and metabolism, here we demonstrate TOR Complex1 (TORC1) regulates efficient group cell movement of BCs. Employing live cell imaging, genetics, and tissue immunohistochemistry, we demonstrate TOR functions through transcription factor Reptor to modulate the Death-associated inhibitor of apoptosis 1 (DIAP1) in mediating efficient movement of BCs. Coincidentally, Rapamycin-treated myeloblast Kasumi-1 cells exhibit lower levels of transcript for DIAP-1 homolog, Baculoviral IAP repeat-containing 2 (BIRC2), similar to what is observed in flies.
    Keywords:   Drosophila oogenesis; BC migration; BIRC2; Collective cell movement; DIAP1; REPTOR; TOR signalling
    DOI:  https://doi.org/10.1242/dev.204612
  20. FASEB J. 2025 Aug 31. 39(16): e70928
    Psrc1 Ensures Proper Spindle Assembly and Chromosome Segregation During Mouse Oocyte Maturation.
    Wang Xin-Jie, Wei Kang-Na, Liu Yu-Qing, Zeng Zhao-Cheng, Liang Hui-Sheng, Jiang Jiang, Zeng Li-Xin, Wang Hai-Long.
      The proper assembly and migration of the spindle and the correct segregation of the chromosomes play a crucial role in oocyte quality. In somatic cells, Psrc1 regulates spindle dynamics and mitotic progression; however, its functions in oocyte meiosis have not been fully elucidated. This study aims to elucidate the functions of Psrc1 in mouse oocyte meiosis. To understand PSRC1's function, immunofluorescence staining was used to examine its location in the oocyte and to analyze phenotype after protein knockdown. Western blotting was used to examine the PSRC1 protein abundance. The treatment of oocytes with Taxol and nocodazole demonstrated that PSRC1 co-localizes with spindle microtubules. Psrc1 was knocked down by siRNA injection, and myc-Psrc1 mRNA was overexpressed via plasmid construction. In the current study, we demonstrated for the first time that PSRC1 is located at the poles of the spindle at all stages of mouse oocyte development. Knockdown of Psrc1 leads to abnormal spindle morphology, continuous activation of the spindle assembly checkpoint (SAC) protein, abnormal kinetochore-microtubule (K-M) attachments, and an increased aneuploidy rate. Surprisingly, either knockdown or overexpression of Psrc1 also causes abnormal spindle assembly and increases the rate of large polar bodies. To summarize, Psrc1 is essential for spindle assembly and chromosome segregation during mouse oocyte maturation.
    Keywords:   Psrc1 ; meiosis; mice; oocyte; spindle
    DOI:  https://doi.org/10.1096/fj.202501813R
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