bims-cebooc Biomed News
on Cell biology of oocytes
Issue of 2025–01–05
twelve papers selected by
Gabriele Zaffagnini, Universität zu Köln
  1. Spatiotemporal dynamics of early oogenesis in pigs.
  2. Compartmentalized localization of perinuclear proteins within germ granules in C. elegans.
  3. MARTRE family proteins negatively regulate CCR4-NOT activity to protect poly(A) tail length and promote translation of maternal mRNA.
  4. A phosphate-binding pocket in cyclin B3 is essential for XErp1/Emi2 degradation in meiosis I.
  5. CALB1 and RPL23 Are Essential for Maintaining Oocyte Quality and Function During Aging.
  6. PATL2 mutations affect human oocyte maternal mRNA homeostasis and protein interactions in cell cycle regulation.
  7. GPI transamidase complex is required for primordial germ cell migration and development in zebrafish.
  8. NaP-TRAP reveals the regulatory grammar in 5'UTR-mediated translation regulation during zebrafish development.
  9. A long noncoding RNA with enhancer-like function in pig zygotic genome activation.
  10. Oogenesis involves a novel nuclear envelop remodeling mechanism in Schmidtea mediterranea.
  11. X*Y females exhibit steeper reproductive senescence in the African pygmy mouse.
  12. Physiological premature aging of ovarian blood vessels leads to decline in fertility in middle-aged mice.
  1. Genome Biol. 2025 Jan 02. 26(1): 2
    Spatiotemporal dynamics of early oogenesis in pigs.
    Wei Ge, Yi-Lin Niu, Yu-Kang Li, Li Li, Han Wang, Wen-Wen Li, Tian Qiao, Yan-Ni Feng, Yu-Qing Feng, Jing Liu, Jun-Jie Wang, Xiao-Feng Sun, Shun-Feng Cheng, Lan Li, Wei Shen.
       BACKGROUND: In humans and other mammals, the process of oogenesis initiates asynchronously in specific ovarian regions, leading to the localization of dormant and growing follicles in the cortex and medulla, respectively; however, the current understanding of this process remains insufficient.
    RESULTS: Here, we integrate single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) to comprehend spatial-temporal gene expression profiles and explore the spatial organization of ovarian microenvironments during early oogenesis in pigs. Projection of the germ cell clusters at different stages of oogenesis into the spatial atlas unveils a "cortical to medullary (C-M)" distribution of germ cells in the developing porcine ovaries. Cross-species analysis between pigs and humans unveils a conserved C-M distribution pattern of germ cells during oogenesis, highlighting the utility of pigs as valuable models for studying human oogenesis in a spatial context. RNA velocity analysis with ST identifies the molecular characteristics and spatial dynamics of granulosa cell lineages originating from the cortical and medullary regions in pig ovaries. Spatial co-occurrence analysis and intercellular communication analysis unveils a distinct cell-cell communication pattern between germ cells and somatic cells in the cortex and medulla regions. Notably, in vitro culture of ovarian tissues verifies that intercellular NOTCH signaling and extracellular matrix (ECM) proteins played crucial roles in initiating meiotic and oogenic programs, highlighting an underappreciated role of ovarian microenvironments in orchestrating germ cell fates.
    CONCLUSIONS: Overall, our work provides insight into the spatial characteristics of early oogenesis and the regulatory role of ovarian microenvironments in germ cell fate within a spatial context.
    Keywords:  Early oogenesis; Microenvironments; Spatiotemporal transcriptomics
    DOI:  https://doi.org/10.1186/s13059-024-03464-8
  2. Dev Cell. 2024 Dec 26. pii: S1534-5807(24)00738-X. [Epub ahead of print]
    Compartmentalized localization of perinuclear proteins within germ granules in C. elegans.
    Xiaona Huang, Xuezhu Feng, Yong-Hong Yan, Demin Xu, Ke Wang, Chengming Zhu, Meng-Qiu Dong, Xinya Huang, Shouhong Guang, Xiangyang Chen.
      Germ granules, or nuage, are RNA-rich condensates that are often docked on the cytoplasmic surface of germline nuclei. C. elegans perinuclear germ granules are composed of multiple subcompartments, including P granules, Mutator foci, Z granules, SIMR foci, P -bodies, and E granules. Although many perinuclear proteins have been identified, their precise localization within the subcompartments of the germ granule is still unclear. Here, we systematically labeled perinuclear proteins with fluorescent tags via CRISPR-Cas9 technology. Using this nematode strain library, we identified a series of proteins localized in Z or E granules and extended the characterization of the D granule. Finally, we found that the LOTUS domain protein MIP-1/EGGD-1 regulated the multiphase organization of the germ granule. Overall, our work identified the germ-granule architecture and redefined the compartmental localization of perinuclear proteins. Additionally, the library of genetically modified nematode strains will facilitate research on C. elegans germ granules.
    Keywords:  C. elegans; D granule; compartmentalization; germ granule; membraneless organelles; perinuclear proteins; phase separation; piRNA; small RNAs
    DOI:  https://doi.org/10.1016/j.devcel.2024.12.016
  3. Nat Commun. 2025 Jan 02. 16(1): 248
    MARTRE family proteins negatively regulate CCR4-NOT activity to protect poly(A) tail length and promote translation of maternal mRNA.
    Jing Yang, Jiachen Bu, Bowen Liu, Yusheng Liu, Zhuqiang Zhang, Ziyi Li, Falong Lu, Bing Zhu, Yingfeng Li.
      The mammalian early embryo development requires translation of maternal mRNA inherited from the oocyte. While poly(A) tail length influences mRNA translation efficiency during the oocyte-to-embryo transition (OET), molecular mechanisms regulating maternal RNA poly(A) tail length are not fully understood. In this study, we identified MARTRE, a previously uncharacterized protein family (MARTRE1-MARTRE6), as regulators expressed during mouse OET that modulate poly(A) tail length. MARTRE inhibits deadenylation through the direct interaction with the deadenylase CCR4-NOT, and ectopic expression of Martre stabilized mRNA by attenuating poly(A) tail shortening. Deletion of the Martre gene locus results in shortened poly(A) tails and decreased translation efficiency of actively translated mRNAs in mouse zygotes, but does not affect maternal mRNA decay. MARTRE proteins thus fine-tune maternal mRNA translation by negatively regulating the deadenylating activity of CCR4-NOT. Moreover, Martre knockout embryos show delayed 2-cell stage progression and compromised preimplantation development. Together, our findings highlight protection of long poly(A) tails from active deadenylation as an important mechanism to coordinate translation of maternal mRNA.
    DOI:  https://doi.org/10.1038/s41467-024-55610-2
  4. EMBO Rep. 2025 Jan 02.
    A phosphate-binding pocket in cyclin B3 is essential for XErp1/Emi2 degradation in meiosis I.
    Rebecca Schunk, Marc Halder, Michael Schäfer, Elijah Johannes, Andreas Heim, Andreas Boland, Thomas U Mayer.
      To ensure the correct euploid state of embryos, it is essential that vertebrate oocytes await fertilization arrested at metaphase of meiosis II. This MII arrest is mediated by XErp1/Emi2, which inhibits the ubiquitin ligase APC/C (anaphase-promoting complex/cyclosome). Cyclin B3 in complex with Cdk1 (cyclin-dependent kinase 1) is essential to prevent an untimely arrest of vertebrate oocytes in meiosis I by targeting XErp1/Emi2 for degradation. Yet, the molecular mechanism of XErp1/Emi2 degradation in MI is not well understood. Here, by combining TRIM-Away in oocytes with egg extract and in vitro studies, we demonstrate that a hitherto unknown phosphate-binding pocket in cyclin B3 is essential for efficient XErp1/Emi2 degradation in meiosis I. This pocket enables Cdk1/cyclin B3 to bind pre-phosphorylated XErp1/Emi2 facilitating further phosphorylation events, which ultimately target XErp1/Emi2 for degradation in a Plk1- (Polo-like kinase 1) dependent manner. Key elements of this degradative mechanism are conserved in frog and mouse. Our studies identify a novel, evolutionarily conserved determinant of Cdk/cyclin substrate specificity essential to prevent an untimely oocyte arrest at meiosis I with catastrophic consequences upon fertilization.
    Keywords:  APC/C; Cyclin B3; Emi2; Phosphate-binding Pocket; XErp1
    DOI:  https://doi.org/10.1038/s44319-024-00347-8
  5. Aging Cell. 2025 Jan 02. e14466
    CALB1 and RPL23 Are Essential for Maintaining Oocyte Quality and Function During Aging.
    Yingxue Han, Zihuan Du, Hao Wu, Rong Zhao, Jikang Liu, Shuai Gao, Shenming Zeng.
      With advancing age, significant changes occur in the female reproductive system, the most notable of which is the decline in oocyte quality, a key factor affecting female fertility. However, the mechanisms underlying oocyte aging remain poorly understood. In this study, we obtained oocytes from aged and young female mice and performed single-cell transcriptome sequencing, comparing our findings with existing proteomic analyses. Our analysis revealed that one of the primary characteristics of aging oocytes is the disruption of calcium ion homeostasis. Specifically, we identified two key genes involved in the oocyte aging process, Calb1 and Rpl23. Experimental validation demonstrated that knockdown of CALB1 in oocytes led to reduced calcium ion levels in the endoplasmic reticulum and mitochondria, resulting in mitochondrial dysfunction and meiotic defects. Further experiments suggested that RPL23 may function as a downstream gene of CALB1, and its knockdown caused mitochondrial dysfunction, excessive accumulation of reactive oxygen species (ROS), and spindle assembly defects. Notably, overexpression of these two genes in aging oocytes partially rescued the maternal age-related defective phenotypes, underscoring their crucial roles in oocyte aging. This study provides a comprehensive understanding of the specific mechanisms underlying mouse oocyte aging at single-cell resolution, supported by experimental validation, and offers new directions and potential targets for future research into age-related reproductive health issues.
    Keywords:  CALB1; RPL23; aging; calcium; mitochondrial; oocyte
    DOI:  https://doi.org/10.1111/acel.14466
  6. Cell Biosci. 2024 Dec 31. 14(1): 157
    PATL2 mutations affect human oocyte maternal mRNA homeostasis and protein interactions in cell cycle regulation.
    Yin-Li Zhang, Zhanhong Hu, Huifang Jiang, Jiamin Jin, Yan Zhou, Mengru Lai, Peipei Ren, Siya Liu, Ying-Yi Zhang, Yan Rong, Wei Zheng, Shen Zhang, Xiaomei Tong, Songying Zhang.
       BACKGROUND: Oocyte maturation defect (OMD) and early embryonic arrest result in female infertility. Previous studies have linked biallelic mutations in the PATL2 gene to OMD, yet the underlying mechanism remains largely unknown.
    RESULTS: This study uncovers three novel mutations (c.1201G > T, c.1284delA and c.1613 + 2_1613 + 3insGT) and three reported mutations (c.1204 C > T, c.1271T > C, c.223 - 14_223-2delCCCTCCTGTTCCA) in the PATL2 gene across five unrelated individuals exhibiting OMD, oocyte death, and early embryonic arrest. RNA sequencing revealed that PATL2 mutations decreased mRNA storage in human germinal vesicle (GV) oocytes and impeded mRNA decay during maturation and in early embryos. We demonstrate that PATL2 interacts with CPEB1 and TUT7 in human oocytes to maintain mRNA homeostasis. Additionally, we observed a reduction in CCNB1 and CCNE1 mRNA levels in PATL2-mutant GV oocytes, which may be linked to GV arrest. Employing both wild-type and mutated PATL2V401F/R402W variants, we characterized the protein interactome of PATL2, identifying disruptions of PATL2V401F/R402W variants predominantly affecting cell cycle-related proteins, including CDC23, APC1 and MAD2L1. PATL2's interaction with and stabilization of CDC23 in oocytes may elucidate the mechanisms behind the mutation-induced MI arrest. PALT2 is required for the efficient mRNA translation and it maintains the protein level of CDC23, APC1 and MAD2L1 in mouse GV oocyte.
    CONCLUSION: PATL2 plays a critical role in regulating mRNA accumulation and decay in human oocytes, potentially through interactions with CPEB1 and TUT7, respectively. Mutations in PATL2 lead to oocyte meiosis defects by affecting the mRNA accumulation, mRNA translation, and direct binding to and stabilizing proteins related to cell cycle regulation, such as CCNB1 and CDC23. This study expands the mutational spectrum of PATL2 and provides new insights into the molecular mechanisms underlying PATL2 mutation-associated oocyte maturation disorders.
    Keywords:   PATL2 mutation; CDC23; TUT7; mRNA decay; mRNA storage
    DOI:  https://doi.org/10.1186/s13578-024-01341-2
  7. J Mol Cell Biol. 2024 Dec 31. pii: mjae058. [Epub ahead of print]
    GPI transamidase complex is required for primordial germ cell migration and development in zebrafish.
    Weiying Zhang, Yaqi Li, Jing Chen, Likun Yao, Bingjie Zhang, Lin Zhang, Boqi Liu, Weimin Shen, Anming Meng, Xiaotong Wu.
      Proteins without transmembrane domains could be anchored to the cell surface for regulating various biological processes when covalently linked to glycosylphosphatidylinositol (GPI) molecules by the GPI transamidase (GPIT) complex. However, it remains poorly understood whether and how the GPIT complex affects primordial germ cell (PGC) development. In this study, we report the important roles of GPI transamidase in PGC migration and development in zebrafish embryos. Mutation of pigu or pigk, both encoding essential GPIT complex subunits, resulted in defective PGC migration with ectopically located PGCs and reduction of PGC counts. Notably, a detailed analysis of filopodia in PGCs revealed the attenuated polarity of filopodia distribution along the migration direction in mutant embryos. PGC transplantation and PGC-specific rescue experiments demonstrated that both PGC and somatic cell-expressed Pigu are required for PGC migration. Furthermore, expression levels of PGC-specific genes decreased in pigu mutant PGCs with the derepression of somatic cell genes. Hence, we propose that the GPIT complex plays a critical role during PGC migration and development.
    Keywords:  Cell migration; GPI transamidase complex; Pigu; Primordial germ cell; Zebrafish
    DOI:  https://doi.org/10.1093/jmcb/mjae058
  8. Nat Commun. 2024 Dec 30. 15(1): 10898
    NaP-TRAP reveals the regulatory grammar in 5'UTR-mediated translation regulation during zebrafish development.
    Ethan C Strayer, Srikar Krishna, Haejeong Lee, Charles Vejnar, Nils Neuenkirchen, Amit Gupta, Jean-Denis Beaudoin, Antonio J Giraldez.
      The cis-regulatory elements encoded in an mRNA determine its stability and translational output. While there has been a considerable effort to understand the factors driving mRNA stability, the regulatory frameworks governing translational control remain more elusive. We have developed a novel massively parallel reporter assay (MPRA) to measure mRNA translation, named Nascent Peptide Translating Ribosome Affinity Purification (NaP-TRAP). NaP-TRAP measures translation in a frame-specific manner through the immunocapture of epitope tagged nascent peptides of reporter mRNAs. We benchmark NaP-TRAP to polysome profiling and use it to quantify Kozak strength and the regulatory landscapes of 5' UTRs in the developing zebrafish embryo and in human cells. Through this approach we identified general and developmentally dynamic cis-regulatory elements, as well as potential trans-acting proteins. We find that U-rich motifs are general enhancers, and upstream ORFs and GC-rich motifs are global repressors of translation. We also observe a translational switch during the maternal-to-zygotic transition, where C-rich motifs shift from repressors to prominent activators of translation. Conversely, we show that microRNA sites in the 5' UTR repress translation following the zygotic expression of miR-430. Together these results demonstrate that NaP-TRAP is a versatile, accessible, and powerful method to decode the regulatory functions of UTRs across different systems.
    DOI:  https://doi.org/10.1038/s41467-024-55274-y
  9. J Mol Cell Biol. 2025 Jan 02. pii: mjae061. [Epub ahead of print]
    A long noncoding RNA with enhancer-like function in pig zygotic genome activation.
    Renyue Wei, Yanbin Yue, Yinhuan Wu, Chenyuan Zhang, Junxue Jin, Zhonghua Liu, Jiaqiang Wang.
      The zygotic genome activation (ZGA) is crucial for the development of pre-implantation embryos. Long noncoding RNAs (lncRNAs) play significant roles in many biological processes, but the study on their role in the early embryonic development of pigs is limited. In this study, we identify lncFKBPL as an enhancer-type lncRNA essential for pig embryo development. LncFKBPL is expressed from the 4-cell stage to the morula stage in pig embryos, and interference with lncFKBPL leads to a developmental arrest at the 8-cell stage. Mechanistic investigations uncover that lncFKBPL is able to bind to MED8, thereby mediating enhancer activity and regulating FKBPL expression. Additionally, FKBPL interacts with the molecular chaperone protein HSP90AA1, stabilizing CDK9 and boosting its protein-level expression. Elevated CDK9 levels enhance Pol II phosphorylation, facilitating ZGA. Our findings illuminate the role of lncFKBPL as an enhancer lncRNA in pig ZGA regulation and early embryo development, providing a foundation for further exploration in this area.
    Keywords:  lncRNA; porcine; pre-implantation embryonic development; zygotic genome activation
    DOI:  https://doi.org/10.1093/jmcb/mjae061
  10. Dev Biol. 2024 Dec 26. pii: S0012-1606(24)00290-2. [Epub ahead of print]
    Oogenesis involves a novel nuclear envelop remodeling mechanism in Schmidtea mediterranea.
    Longhua Guo, Fengli Guo, Shasha Zhang, An Zeng, Kexi Yi, Melainia McClain, Claus-D Kuhn, Tari Parmely, Alejandro Sánchez Alvarado.
      The cell nuclei of Ophisthokonts, the eukaryotic supergroup defined by fungi and metazoans, is remarkable in the constancy of their double-membraned structure in both somatic and germ cells. Such remarkable structural conservation underscores common and ancient evolutionary origins. Yet, the dynamics of disassembly and reassembly displayed by Ophisthokont nuclei vary extensively. Besides closed mitosis in fungi and open mitosis in some animals, little is known about the evolution of nuclear envelope remodeling dynamics during oogenesis. Here, we uncovered a novel form of nuclear envelope remodeling as oocytes are formed in the flatworm Schmidtea mediterranea. From zygotene to metaphase II, both nuclear envelope (NE) and peripheral endoplasmic reticulum (ER) expand notably in size, likely involving de novo membrane synthesis. 3-D electron microscopy reconstructions demonstrated that the NE transforms itself into numerous double-membraned vesicles similar in membrane architecture to NE doublets in mammalian oocytes after germinal vesicle breakdown. The vesicles are devoid of nuclear pore complexes and DNA, yet are loaded with nuclear proteins, including a planarian homologue of PIWI, a protein essential for the maintenance of stem cells in this and other organisms. Our data contribute a new model to the canonical view of NE dynamics and suggest important roles of NE remodeling in planarian oogenesis.
    DOI:  https://doi.org/10.1016/j.ydbio.2024.12.018
  11. Proc Natl Acad Sci U S A. 2025 Jan 07. 122(1): e2412609121
    X*Y females exhibit steeper reproductive senescence in the African pygmy mouse.
    Jean-François Lemaître, Yann Voituron, Léa Herpe, Frédéric Veyrunes.
      A wave of studies has recently emphasized the influence of sex chromosomes on both lifespan and actuarial senescence patterns across vertebrates and invertebrates. Basically, the heterogametic sex (XY males in XX/XY systems or ZW females in ZW/ZZ systems) typically displays a lower lifespan and a steeper rate of actuarial senescence than the homogametic sex. However, whether these effects extend to the senescence patterns of other phenotypic traits or physiological functions is yet to be determined. Here, we investigated whether sex chromosomes modulate reproductive senescence using females from the African pygmy mouse (Mus minutoides). This biological model exhibits an odd sex determining system with a third, feminizing sex chromosome, X*, resulting in three distinct female genotypes (XX, X*X, or X*Y) that coexist in natural populations. We found that the rate of senescence in litter size at birth is much more pronounced in heterogametic X*Y females than in homogametic XX or X*X females that may support the unguarded X or toxic Y hypotheses and can be directly linked to the complex and unique X*Y phenotype. A decrease in neonatal survival with mother's age has also been found, but this decline is not different between the three female genotypes.
    Keywords:  Mus minutoides; litter size; neonatal survival; reproductive ageing
    DOI:  https://doi.org/10.1073/pnas.2412609121
  12. Nat Commun. 2025 Jan 02. 16(1): 72
    Physiological premature aging of ovarian blood vessels leads to decline in fertility in middle-aged mice.
    Lu Mu, Ge Wang, Xuebing Yang, Jing Liang, Huan Tong, Lingyu Li, Kaiying Geng, Yingnan Bo, Xindi Hu, Ruobing Yang, Xueqiang Xu, Yan Zhang, Hua Zhang.
      Ovarian function declines significantly as females enter middle-age, but the mechanisms underlying this decline remain unclear. Here, we utilize whole-organ imaging to observe a notable decrease in ovarian blood vessel (oBV) density and angiogenesis intensity of middle-aged mice. This leads to a diminished blood supply to the ovaries, resulting in inadequate development and maturation of ovarian follicles. Utilizing genetic-modified mouse models, we demonstrate that granulosa cell secreted VEGFA governs ovarian angiogenesis, but the physiological decline in oBV is not attributed to VEGFA insufficiency. Instead, through single-cell sequencing, we identify the aging of the ovarian vascular endothelium as the primary factor contributing to oBV decline. Consequently, the administration of salidroside, a natural compound that is functional to reverse oBV aging and promote ovarian angiogenesis, significantly enhances ovarian blood supply and improve fertility in older females. Our findings highlight that enhancing oBV function is a promising strategy to boost fertility in females.
    DOI:  https://doi.org/10.1038/s41467-024-55509-y
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