bims-cebooc Biomed News
on Cell biology of oocytes
Issue of 2025–01–19
eight papers selected by
Gabriele Zaffagnini, Universität zu Köln
  1. Maternal ELL3 loss-of-function leads to oocyte aneuploidy and early miscarriage.
  2. The Balbiani body is formed by microtubule-controlled molecular condensation of Buc in early oogenesis.
  3. Extensive homologous recombination safeguards oocyte genome integrity in mammals.
  4. Single-cell RNA-seq identifies protracted mouse germline X chromosome reactivation dynamics directed by a PRC2-dependent mechanism.
  5. Deciphering transcription activity of mammalian early embryos unveils on/off of zygotic genome activation by protein translation/degradation.
  6. BMP and STRA8 act collaboratively to ensure correct mitotic-to-meiotic transition in the fetal mouse ovary.
  7. The piRNA protein Asz1 is essential for germ cell and gonad development in zebrafish and exhibits differential necessities in distinct types of germ granules.
  8. The WIRS motifs in Fat2 are required for Drosophila egg chamber rotation but not for elongation.
  1. Nat Struct Mol Biol. 2025 Jan 16.
    Maternal ELL3 loss-of-function leads to oocyte aneuploidy and early miscarriage.
    Shiqi Zhu, Peng Xie, Yi Yang, Yan Wang, Chuanxin Zhang, Yu Zhang, Shuhan Si, Jin Zhang, Jingjing He, Hao Si, Ke Fang, Binbin Ma, Xu Jiang, Lindi Huang, Jiamin Li, Tian Min, Beihong Zheng, Lincui Da, Dianliang Lin, Kun Gao, Yuanyuan Li, Mingtao Huang, Fengchang Qiao, Haiqin Huo, Haoyang Feng, Han Zhao, Zijiang Chen, Zhengfeng Xu, Jing Xie, Hua Cao, Jin Liu, Xuebiao Yao, Wei Xie, Yan Sun, Keliang Wu, Bo Xiong, Ping Hu, Zhuojuan Luo, Chengqi Lin.
      Up to an estimated 10% of women experience miscarriage in their lifetimes. Embryonic aneuploidy is a leading cause for miscarriage, infertility and congenital defects. Here we identify variants of ELL3, a gene encoding a transcription elongation factor, in couples who experienced consecutive early miscarriages due to embryonic aneuploidy. Maternal ELL3 knockout leads to mouse oocyte aneuploidy, subfertility and miscellaneous embryonic defects. Mechanistically, we find that ELL3 localizes to the spindle during meiosis, and that ELL3 depletion in both mouse and human oocytes increases the incidence of meiotic spindle abnormality. ELL3 coordinates with TPX2 to ensure the proper function of the microtubule motor KIF11. Live imaging analysis shows that ELL3 is paramount for promoting spindle assembly and driving chromosome movement. Together, our findings implicate maternal ELL3 deficiency in causing oocyte aneuploidy and early miscarriage.
    DOI:  https://doi.org/10.1038/s41594-024-01471-8
  2. Curr Biol. 2025 Jan 06. pii: S0960-9822(24)01623-3. [Epub ahead of print]
    The Balbiani body is formed by microtubule-controlled molecular condensation of Buc in early oogenesis.
    Swastik Kar, Rachael Deis, Adam Ahmad, Yoel Bogoch, Avichai Dominitz, Gal Shvaizer, Esther Sasson, Avishag Mytlis, Ayal Ben-Zvi, Yaniv M Elkouby.
      Vertebrate oocyte polarity has been observed for two centuries and is essential for embryonic axis formation and germline specification, yet its underlying mechanisms remain unknown. In oocyte polarization, critical RNA-protein (RNP) granules delivered to the oocyte's vegetal pole are stored by the Balbiani body (Bb), a membraneless organelle conserved across species from insects to humans. However, the mechanisms of Bb formation are still unclear. Here, we elucidate mechanisms of Bb formation in zebrafish through developmental biomolecular condensation. Using super-resolution microscopy, live imaging, biochemical, and genetic analyses in vivo, we demonstrate that Bb formation is driven by molecular condensation through phase separation of the essential intrinsically disordered protein Bucky ball (Buc). Live imaging, molecular analyses, and fluorescence recovery after photobleaching (FRAP) experiments in vivo reveal Buc-dependent changes in the Bb condensate's dynamics and apparent material properties, transitioning from liquid-like condensates to a solid-like stable compartment. Furthermore, we identify a multistep regulation by microtubules that controls Bb condensation: first through dynein-mediated trafficking of early condensing Buc granules, then by scaffolding condensed granules, likely through molecular crowding, and finally by caging the mature Bb to prevent overgrowth and maintain shape. These regulatory steps ensure the formation of a single intact Bb, which is considered essential for oocyte polarization and embryonic development. Our work offers insight into the long-standing question of the origins of embryonic polarity in non-mammalian vertebrates, supports a paradigm of cellular control over molecular condensation by microtubules, and highlights biomolecular condensation as a key process in female reproduction.
    Keywords:  Oocyte development; RNP granules; Zebrafish oogenesis; balbiani body; cell polarity; mictotubules; molecular condensation; ovary
    DOI:  https://doi.org/10.1016/j.cub.2024.11.056
  3. Nucleic Acids Res. 2025 Jan 11. pii: gkae1304. [Epub ahead of print]53(2):
    Extensive homologous recombination safeguards oocyte genome integrity in mammals.
    Huiwen Cao, Cheng Qiu, Anxuan Fang, Jianzhou Shang, Wei Xu, Lugeng He, Xing Duan, Qianting Zhang, Chao Yu.
      Meiosis in mammalian oocytes is interrupted by a prolonged arrest at the germinal vesicle stage, during which oocytes have to repair DNA lesions to ensure genome integrity or otherwise undergo apoptosis. The FIRRM/FLIP-FIGNL1 complex dissociates RAD51 from the joint DNA molecules in both homologous recombination (HR) and DNA replication. However, as a type of non-meiotic, non-replicative cells, whether this RAD51-dismantling mechanism regulates genome integrity in oocytes remains elusive. Here, we show that FIRRM/FLIP is required for disassembly of RAD51-filaments and maintenance of genome integrity in oocytes. Deletion of FIRRM in oocytes leads to formation of massive nuclear RAD51 foci in oocytes of primordial follicles and activated follicles in mice. These RAD51 foci colocalize with the sites of DNA damage repair, as indicated by RPA2 and EdU, suggesting substantial DNA damage and extensive HR in oocytes. Especially in fully-grown FIRRM-deleted oocytes, RAD51 forms a net-like structure. As a consequence, FIRRM-deleted females are infertile due to aberrant homologous chromosome segregation at metaphase I and primordial follicle insufficiency at young adulthood. Hence, our study demonstrates the physiological importance of HR in maintaining genome integrity in oocytes.
    DOI:  https://doi.org/10.1093/nar/gkae1304
  4. Dev Cell. 2025 Jan 08. pii: S1534-5807(24)00767-6. [Epub ahead of print]
    Single-cell RNA-seq identifies protracted mouse germline X chromosome reactivation dynamics directed by a PRC2-dependent mechanism.
    Yaqiong Liu, Xianzhong Lau, Prabhakaran Munusamy, Carlos M Abascal Sherwell Sanchez, Daniel Snell, Mahesh Sangrithi.
      Female primordial germ cells (PGCs) undergo X chromosome reactivation (XCR) during genome-wide reprogramming. XCR kinetics and dynamics are poorly understood at a molecular level. Here, we apply single-cell RNA sequencing and chromatin profiling on germ cells from F1 mouse embryos, performing a precise appraisal of XCR spanning from migratory-stage PGCs to gonadal germ cells. Establishment of germ cell sexual dimorphism and X chromosome dosage compensation states in vivo are temporally linked to XCR. Allele-specific analysis evidence that the reactivating X chromosome is minimally active in embryonic day (E)9.5 female PGCs, reactivates gradually, and reaches parity to the active X chromosome in E16.5 oogonia. While Xist is repressed from E10.5 onward, epigenetic memory of X inactivation persists from self-sustained polycomb repressive complex 2 (PRC2) activity. The reactivating X is asymmetrically enriched for histone 3-lysine-27-trimethylation (H3K27me3) at E13.5, which is later reversed, permitting germline gene expression. Our findings relate XCR with PRC2 function in promoting female meiosis.
    Keywords:  PRC2; X chromosome reactivation; allele-specific expression; dosage compensation; genome-wide reprogramming; germ cells; single-cell RNA-seq
    DOI:  https://doi.org/10.1016/j.devcel.2024.12.028
  5. Cell Rep. 2025 Jan 16. pii: S2211-1247(24)01566-3. [Epub ahead of print]44(1): 115215
    Deciphering transcription activity of mammalian early embryos unveils on/off of zygotic genome activation by protein translation/degradation.
    Yi-Ran Zhang, Shi-Meng Guo, Xiao-Yan Shi, Yi-Wen Ding, Huai-Biao Li, Lei Li, Jia-Wei Xu, Ximiao He, Bing-Xin Ma, Ying Yin, Li-Quan Zhou.
      Quantification of transcription activities in mammalian preimplantation embryos is challenging due to a huge amount of maternally stored transcripts and paucity of research materials. Here, we investigate genome-wide transcription activities of mouse and human preimplantation embryos by quantifying elongating RNA polymerase II. Two transcriptional waves are identified in early mouse embryos, with summits at the 2-cell and 8-cell stages. Gene collections with different expression patterns are obtained, with genes mainly transcribed at the mouse early/late 2-cell stage designated as zygotic genome activation-early/late 2-cell (ZGA-E2C/L2C). ZGA-E2C genes are short and have low promoter CpG density. Protein translation/degradation not only regulates transcription activity through stepwise orchestration of histone modifications, transcriptional initiation, and elongation in early mouse embryos but also controls on/off switching of ZGA-E2C/L2C genes in maternal aged mouse embryos. Genes mainly transcribed at the mouse 2-cell stage can also be transcribed as early as the human 2-cell stage.
    Keywords:  CP: Developmental biology; CP: Molecular biology; embryo; maternal aging; preimplantation; transcription activity; zygotic genome activation
    DOI:  https://doi.org/10.1016/j.celrep.2024.115215
  6. Development. 2025 Jan 16. pii: dev.204227. [Epub ahead of print]
    BMP and STRA8 act collaboratively to ensure correct mitotic-to-meiotic transition in the fetal mouse ovary.
    Fiona K M Cheung, Chun-Wei Allen Feng, Clare Crisp, Yuji Mishina, Cassy M Spiller, Josephine Bowles.
      A successful mitosis-to-meiosis transition in germ cells is essential for fertility in sexually reproducing organisms. In mice and humans, it is established that expression of STRA8 is critical for meiotic onset in both sexes. Here we show that BMP signalling is also essential, not for STRA8 induction but for correct meiotic progression in female mouse fetal germ cells. Largely in agreement with evidence from primordial germ cell-like cells (PGCLCs) in vitro, germ cell-specific deletion of BMP receptor 1A (BMPR1A; ALK3) caused aberrant retention of pluripotency marker OCT4 and meiotic progression was compromised; however, the timely onset of Stra8/STRA8 expression was unaffected. Comparing the transcriptomes of Bmpr1a-cKO and Stra8-null models, we reveal interplay between the effects of BMP signalling and STRA8 function. Our results verify a role for BMP signalling in instructing germ cell meiosis in female mice in vivo, and shed light on the regulatory mechanisms underlying fetal germ cell development.
    Keywords:  BMP signalling; Fetal ovarian germ cell; Fetal ovary; Mammalian reproduction; Mitosis-to-meiosis transition; STRA8
    DOI:  https://doi.org/10.1242/dev.204227
  7. PLoS Genet. 2025 Jan 13. 21(1): e1010868
    The piRNA protein Asz1 is essential for germ cell and gonad development in zebrafish and exhibits differential necessities in distinct types of germ granules.
    Adam Ahmad, Yoel Bogoch, Gal Shvaizer, Noga Guler, Karine Levy, Yaniv M Elkouby.
      Germ cells are essential for fertility, embryogenesis, and reproduction. Germline development requires distinct types of germ granules, which contains RNA-protein (RNP) complexes, including germ plasm in embryos, piRNA granules in gonadal germ cells, and the Balbiani body (Bb) in oocytes. However, the regulation of RNP assemblies in zebrafish germline development are still poorly understood. Asz1 is a piRNA protein in Drosophila and mice. Zebrafish Asz1 localizes to both piRNA and Bb granules, with yet unknown functions. Here, we hypothesized that Asz1 functions in germ granules and germline development in zebrafish. We generated asz1 mutant fish to determine the roles of Asz1 in germ cell development. We show that Asz1 is dispensable for somatic development, but essential for germ cell and gonad development. asz1-/- fish developed exclusively as sterile males with severely underdeveloped testes that lacked germ cells. In asz1 mutant juvenile gonads, germ cells undergo extensive apoptosis, demonstrating that Asz1 is essential for germ cell survival. Mechanistically, we provide evidence to conclude that zygotic Asz1 is not required for primordial germ cell specification or migration to the gonad, but is essential during post-embryonic gonad development, likely by suppressing the expression of germline transposons. Increased transposon expression and mis-organized piRNA granules in asz1 mutants, argue that zebrafish Asz1 functions in the piRNA pathway. We generated asz1;tp53 fish to partially rescue ovarian development, revealing that Asz1 is also essential for oogenesis. We further showed that in contrast with piRNA granules, Asz1 is dispensable for Bb granule formation, as shown by normal Bb localization of Buc and dazl. By uncovering Asz1 as an essential regulator of germ cell survival and gonadogenesis in zebrafish, and determining its differential necessity in distinct germ granule types, our work advances our understanding of the developmental genetics of reproduction and fertility, as well as of germ granule biology.
    DOI:  https://doi.org/10.1371/journal.pgen.1010868
  8. Development. 2025 Jan 15. pii: DEV204201. [Epub ahead of print]152(2):
    The WIRS motifs in Fat2 are required for Drosophila egg chamber rotation but not for elongation.
    Akanksha Bhatt, Valentin Ruffine, Uwe Töpfer, Jinhee Ryu, Elisabeth Fischer-Friedrich, Christian Dahmann.
      The elongation of tissues and organs is important for proper morphogenesis in animal development. In Drosophila ovaries, the elongation of egg chambers involves aligned Collagen IV fiber-like structures, a gradient of extracellular matrix stiffness and actin-based protrusion-driven collective cell migration, leading to the rotation of the egg chamber. Egg chamber elongation and rotation depend on the atypical cadherin Fat2. Fat2 contains in its intracellular region three WRC interacting receptor sequence (WIRS) motifs, which previously had been shown to bind to the WAVE regulatory complex (WRC), a conserved actin regulator. Here, we show that in fat2 mutant flies lacking the WIRS motifs, egg chambers fail to rotate and Collagen IV fiber-like structures are impaired, yet a gradient of extracellular matrix stiffness is established and egg chambers properly elongate. We conclude that the WIRS motifs are required for egg chamber rotation and that egg chamber rotation might be a prerequisite for proper formation of Collagen IV fiber-like structures. Egg chamber rotation, however, is dispensable for extracellular matrix stiffness gradient formation and for egg chamber elongation.
    Keywords:   Drosophila ; Atomic force microscopy; Basement membrane; Collagen; Egg chamber; Fat2
    DOI:  https://doi.org/10.1242/dev.204201
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