bims-cebooc 2025-05-04 papers

bims-cebooc

Biomed News

on Cell biology of oocytes

Issue of 2025–05–04
twelve papers selected by
Gabriele Zaffagnini, Universität zu Köln

RNA G-quadruplex removal promotes a translational switch after meiosis resumption.
Oocyte development: it's all about quality.
Programmed mitophagy at the oocyte-to-zygote transition promotes 1 species immortality.
The C-terminal domain of Emi2 conjugated to cell-penetrating peptide activates mouse oocyte.
FTDC1/2, oocyte-specific cofactors of DNMT1 required for epigenetic regulation and embryonic development.
Rbm24a dictates mRNA recruitment for germ granule assembly in zebrafish.
The role of granulosa cells in oocyte development and aging: Mechanisms and therapeutic opportunities.
Paternal effects on telomere integrity during the sperm-to-embryo transition.
Cathepsin B Regulates Ovarian Reserve Quality and Quantity via Mitophagy by Modulating IGF1R Turnover.
Maternal ovo represses the expression of transposable elements in adult ovaries.
Primordial germ cells as a potential model for understanding (Nutri) epigenetic - metabolic interactions: a mini review.
Sperm meet the elevated energy demands to attain fertilization competence by increasing flux through aldolase.

Nucleic Acids Res. 2025 Apr 22. pii: gkaf067. [Epub ahead of print]53(8):

RNA G-quadruplex removal promotes a translational switch after meiosis resumption.

Qiong-Wen Lu, Shao-Yuan Liu, Xiu-Quan Liao, Jing Chen, Zhi-Yan Jiang, Yu-Ke Wu, Heng-Yu Fan, Yu-Jing Lu, Qian-Qian Sha.

Oocyte maturation-coupled mRNA post-transcriptional regulation is essential for the establishment of developmental potential. Previously, oocyte mRNA translation efficiencies focused on the trans-regulation of key RNA-binding protein (RBPs), rarely related to RNA structure. RNA G-quadruplexes (rG4s) are four-stranded RNA secondary structures involved in many different aspects of RNA metabolism. In this study, we have developed a low-input technique for rG4 detection (G4-LACE-seq) in mouse oocytes and found that rG4s were widely distributed in maternal transcripts, with enrichment in untranslated regions, and they underwent transcriptome-wide removal during meiotic maturation. The rG4-selective small-molecule ligand BYBX stabilized rG4s in the oocyte transcriptome and impaired spindle assembly and meiotic cell cycle progression. The proteomic spectrum results revealed that rG4 accumulation weakened the binding of a large number of RBPs to mRNAs, especially those associated with translational initiation. Ribosomal immunoprecipitation and translational reporter assays further proved that rG4s in the untranslated regions negatively affected the translational efficiency of key maternal mRNAs. Overexpression DEAH/RHA family helicase-36 partially reverses BYBX-induced oocyte developmental defects, suggesting its importance in rG4 regulation. Collectively, this study describes the distribution, dynamic changes, and regulation of rG4s in the mouse maternal transcriptome. Before meiosis resumption, a large number of rG4s in oocytes are necessary to maintain the translatome at a low level, and DHX36-mediated rG4 removal promotes a translational switch and is required for successful maternal-to-zygotic transition.

DOI: https://doi.org/10.1093/nar/gkaf067
Reprod Biomed Online. 2025 Apr;pii: S1472-6483(25)00011-2. [Epub ahead of print]50(4): 104804

Oocyte development: it's all about quality.

Richard A Anderson, Adele L Marston, Evelyn E Telfer.

  Mammalian fertility depends on the production of an oocyte capable of fertilization and supporting early embryo development. This requires both cytoplasmic and nuclear, i.e. chromosomal, competence, processes that were initiated decades prior to ovulation. Current demographic changes with delayed motherhood are increasingly in conflict with these biological processes. This brief review highlights the key stages in oocyte development, as well as recent findings that continue to inform on how the oocyte is able to maintain function over such a prolonged period. These include minimizing oocyte damage caused by the production of reactive oxygen species, the importance of intercellular communication with the surrounding somatic cells, and the molecular mechanisms that underpin the fidelity of chromosome cohesion and then separation at the resumption of meiosis. Some of these are already approaching clinical testing and interventions, with new approaches in the coming years potentially being able to 'put back the clock' to improve oocyte quality.

Keywords:  Aneuploidy; Cohesin; Meiosis; Oocyte; Ovarian development

DOI:  https://doi.org/10.1016/j.rbmo.2025.104804
Res Sq. 2025 Apr 09. pii: rs.3.rs-6330979. [Epub ahead of print]

Programmed mitophagy at the oocyte-to-zygote transition promotes 1 species immortality.

David Sherwood, Siddharthan Balachandar Thendral, Sasha Bacot, Katherine Morton, Qiuyi Chi, Isabel Kenny-Ganzert, Joel Meyer.

The quality of mitochondria inherited from the oocyte determines embryonic viability, metabolic health throughout progeny lifetime, and future generation endurance. High levels of endogenous reactive oxygen species and exogenous toxicants are threats to mitochondrial DNA (mtDNA) in fully developed oocytes. Deleterious mtDNA is commonly detected in developed oocytes, but is absent in embryos, suggesting the existence of a cryptic purifying selection mechanism. Here we discover that in C. elegans, the onset of oocyte-to-zygote transition (OZT) developmentally triggers a rapid mitophagy event. We show that mitophagy at OZT (MOZT) requires mitochondrial fragmentation, the macroautophagy pathway, and the mitophagy receptor FUNDC1, but not the prevalent mitophagy factors PINK1 and BNIP3. Impaired MOZT leads to increased deleterious mtDNA inheritance and decreases embryonic survival. Inherited mtDNA damage accumulates across generations, leading to the extinction of descendent populations. Thus, MOZT represents a strategy that preserves mitochondrial health during the mother-to-offspring transmission and promotes species continuity.

DOI: https://doi.org/10.21203/rs.3.rs-6330979/v1
Front Cell Dev Biol. 2025 ;13 1578020

The C-terminal domain of Emi2 conjugated to cell-penetrating peptide activates mouse oocyte.

Toru Suzuki.

   Introduction: The cell cycle of ovulated oocytes from various animal species, including mice, arrests at the second meiotic metaphase until fertilization. The meiotic cell cycle must be initiated to initiate embryonic development. Besides natural fertilization, several methods have been developed to activate unfertilized oocytes without sperm. These methods aid both animal production and molecular studies on meiotic regulation, oocyte activation, and embryogenesis. This study aimed to develop a method to activate mouse oocytes using a cell-penetrating peptide based on the knowledge that the C-terminal domain of the meiotic protein Emi2 can resume the arrested meiotic cell cycle.
Methods: This study used female B6D2F1 mice to investigate the effects of a cell-penetrating peptide-fused Emi2 peptide on oocyte activation. Second meiotic metaphase oocytes were collected, cultured, and treated with the peptide or strontium chloride. Pronuclear formation, second polar body extrusion, and blastocyst development were assessed, and statistical significance was determined using Fisher's exact test.
Results: The cell-penetrating peptide activated zona-intact oocytes in a manner dependent on specific amino acid residues and peptide concentrations, which are critical components for cell membrane penetration. Some oocytes did not survive after the peptide treatment, indicating its cytotoxic effects. It has also been confirmed that oocytes activated using this method can develop to the blastocyst stage.
Discussion: The introduction of peptides or functional amino acid sequences using cell-penetrating peptide or related methods could be an alternative for easily performing functional analyses of the activity of target proteins in oocytes.

Keywords:  cell-penetrating peptide; meiotic arrest; mouse; oocyte activation; preimplantation development

DOI:  https://doi.org/10.3389/fcell.2025.1578020
Cell Death Differ. 2025 Apr 28.

FTDC1/2, oocyte-specific cofactors of DNMT1 required for epigenetic regulation and embryonic development.

Congyang Li, Jiashuo Li, Siyu Du, Yunfei Ma, Yueshuai Guo, Xiangzheng Zhang, Bing Wang, Shuai Zhu, Huiqing An, Ming Chen, Junjie Guo, Longsen Han, Juan Ge, Xu Qian, Tim Schedl, Xuejiang Guo, Qiang Wang.

The unique epigenetic patterns during gametogenesis and embryonic development indicate the existence of specialized methylation machinery. In the present study, we describe the discovery of two oocyte-specific cofactors of DNA methyltransferase 1 (DNMT1), encoded by uncharacterized genes, ferritin domain containing 1 and 2 (Ftdc1 and Ftdc2). Genetic ablation of Ftdc1 or Ftdc2 causes midgestation defects and female infertility. FTDC1 or FTDC2 depletion induces the progressive loss of DNA methylation including imprinted regions in early embryos. This loss correlates with a marked reduction in DNMT1 protein due to increased degradation, likely via the ubiquitin-proteasome pathway. Mechanistically, we find that FTDC1, FTDC2 and DNMT1 form a complex by direct interactions, thereby stabilizing each other. Surprisingly, knockout of Ftdc1 or Ftdc2 displayed stronger DNA demethylation phenotypes and earlier embryonic lethality than the Dnmt1-null mutant, implying their unique functions. These data suggest that FTDC1/2 are crucial players specifically involved in maintaining genomic methylation during embryogenesis, offering new insights into the epigenetic control of mammalian development.

DOI: https://doi.org/10.1038/s41418-025-01518-3
EMBO J. 2025 Apr 25.

Rbm24a dictates mRNA recruitment for germ granule assembly in zebrafish.

Yizhuang Zhang, Jiasheng Wang, Hailing Fang, Shuqi Hu, Boya Yang, Jiayi Zhou, Raphaëlle Grifone, Panfeng Li, Tong Lu, Zhengyang Wang, Chong Zhang, Yubin Huang, Dalei Wu, Qianqian Gong, De-Li Shi, Ang Li, Ming Shao.

  The germ granules are ribonucleoprotein (RNP) biomolecular condensates that determine the fate of primordial germ cells (PGCs) and serve as a model for studying RNP granule assembly. Here, we show that the maternal RNA-binding protein Rbm24a is a key factor governing the specific sorting of mRNAs into germ granules. Mechanistically, Rbm24a interacts with the germ plasm component Buc to dictate the specific recruitment of germ plasm mRNAs into phase-separated condensates. Germ plasm particles lacking Rbm24a and mRNAs fail to undergo kinesin-dependent transport toward cleavage furrows where small granules fuse into large aggregates. Therefore, the loss of maternal Rbm24a causes a complete degradation of the germ plasm and the disappearance of PGCs. These findings demonstrate that the Rbm24a/Buc complex functions as a nucleating organizer of germ granules, highlighting an emerging mechanism for RNA-binding proteins in reading and recruiting RNA components into a phase-separated protein scaffold.

Keywords:  Degron; Primordial Germ Cell; RNA Recruitment; Rbm24; Ribonucleoprotein Granule

DOI:  https://doi.org/10.1038/s44318-025-00442-z
Semin Cell Dev Biol. 2025 Apr 28. pii: S1084-9521(25)00024-2. [Epub ahead of print]171 103614

The role of granulosa cells in oocyte development and aging: Mechanisms and therapeutic opportunities.

HaiYang Wang.

  Granulosa cells (GCs) are essential for oocyte maturation, providing metabolic support, hormonal signaling, and structural integrity critical to successful follicular development. However, advancing age disrupts these functions, driven by factors such as increased oxidative stress, mitochondrial dysfunction, and transcriptomic and proteomic alterations. These age-related changes in GCs contribute to compromised oocyte quality, diminished follicular support, and a decline in fertility, particularly in women of advanced maternal age. This review highlights recent progress in understanding the pivotal roles of GCs in maintaining oocyte health, with a focus on the mechanisms underlying their aging-related dysfunction. Furthermore, we explore promising therapeutic strategies, including antioxidant therapies, metabolic modulators, and GC-based rejuvenation techniques, aimed at mitigating the impacts of reproductive aging. By consolidating and analyzing existing research, this review provides valuable perspectives on fertility preservation and factors shaping reproductive outcomes in women of advanced maternal age.

Keywords:  Follicular Microenvironment; Granulosa Cells; Oocyte Development; Reproductive Aging; Therapeutic Interventions

DOI:  https://doi.org/10.1016/j.semcdb.2025.103614
Curr Opin Genet Dev. 2025 Apr 25. pii: S0959-437X(25)00040-1. [Epub ahead of print]93 102348

Paternal effects on telomere integrity during the sperm-to-embryo transition.

Sung-Ya Lin, Mia T Levine.

Telomeres are essential nucleoprotein structures that preserve our terminal DNA sequence and protect chromosome ends from fusion. Our vast knowledge of telomeres comes almost entirely from studies of healthy and diseased somatic cells. However, building evidence suggests that the molecules and mechanisms required for telomere integrity in somatic cells are insufficient to preserve telomere integrity during the sperm-to-embryo transition. Here, we review this growing body of work on telomere 'paternal effects', wherein zygotic telomere integrity is determined not by the genotype of the zygote but instead by the genotype of the father. Direct inheritance of sperm-specific proteins establishes paternal telomere epigenetic identity, while direct inheritance of sperm telomere length contributes to telomere length inheritance. Together, these investigations of telomere integrity through the sperm-to-embryo transition reveal potent paternal effects on zygotic telomere functions, with implications for human infertility.

DOI: https://doi.org/10.1016/j.gde.2025.102348
Aging Cell. 2025 Apr 28. e70066

Cathepsin B Regulates Ovarian Reserve Quality and Quantity via Mitophagy by Modulating IGF1R Turnover.

Aradhana Mohanty, Anjali Kumari, Lava Kumar S, Ajith Kumar, Pravin Birajdar, Rohit Beniwal, Mohd Athar, Kiran Kumar P, H B D Prasada Rao.

  The quality and quantity of the ovarian reserve are meticulously regulated through various cell death pathways to guarantee the availability of high-quality oocytes for fertilization. While apoptosis is recognized for contributing to maintaining ovarian reserve, the involvement of other cell death pathways remains unclear. Employing chemical genetics and proteomics, this study reveals the crucial involvement of Cathepsin B in maintaining the ovarian reserve. Results indicate that apoptosis and autophagy play pivotal roles, and inhibiting these pathways significantly increases follicle numbers. Proteomics reveals a dynamic shift from apoptosis to autophagy during follicular development, with Cathepsin B emerging as a key player in this transition. Inhibiting Cathepsin B not only mimics the augmented oocyte reserve observed with autophagy inhibition but also upregulated IGF1R and AKT-mTOR pathways without compromising fertility in pre- and postpubertal mice. Further, IGF1R inhibition partially compromised the protective effects of Cathepsin B inhibition on oocyte reserves, suggesting their interdependence. This association is further supported by the finding that Cathepsin B can degrade IGF1R in vitro. Moreover, the increased IGF1R levels enhance the oocyte mitochondrial membrane potential via transcriptional regulation of mitochondrial biogenesis and mitophagy genes. Remarkably, this Cathepsin B-dependent ovarian reserve maintenance mechanism is conserved in higher-order vertebrates. Cumulatively, our study sheds valuable light on the intricate interplay of autophagy, Cathepsin B, and growth factors in ovarian reserve maintenance, offering potential therapeutic strategies to delay ovarian aging and preserve fertility.

Keywords:  IGF1R; autophagy; cathepsin B; mitophagy; ovarian reserve

DOI:  https://doi.org/10.1111/acel.70066
Dev Biol. 2025 Apr 23. pii: S0012-1606(25)00109-5. [Epub ahead of print]523 111-114

Maternal ovo represses the expression of transposable elements in adult ovaries.

Makoto Hayashi, Yuica Koga, Yasuhiro Kozono, Satoru Kobayashi.

  In germ cells, repressing transposable elements (TEs) is important to maintain genomic integrity. TE expression and transposition are repressed by PIWI-interacting RNAs (piRNAs). Although many genes for piRNA synthesis have been described, few transcription factors activating their expression have been identified. We previously reported that a transcription factor, maternal Ovo (Ovo-B) protein activates germline-specific gene expression in progenitors of germ cells. In this study, we found that maternal Ovo also activates several genes, including aubergine (aub), for TE silencing. Knocking down maternal Ovo de-repressed TEs in adult ovaries. In addition, embryonic knockdown of aub caused de-repression of TEs in adult Drosophila ovaries. Surprisingly, embryonic knockdown of maternal Ovo affected neither expression of ovo nor its downstream TE-silencing genes in adult ovaries after growth. These results strongly suggest that maternal Ovo is required for TE silencing in ovaries, via transcriptional activation of genes for piRNA synthesis in embryos.

Keywords:  Drosophila; Germline; Ovo; Transposable elements

DOI:  https://doi.org/10.1016/j.ydbio.2025.04.014
Front Cell Dev Biol. 2025 ;13 1576768

Primordial germ cells as a potential model for understanding (Nutri) epigenetic - metabolic interactions: a mini review.

Mariam Ibrahim, Ewa Grochowska, Katarzyna Stadnicka.

  Primordial germ cells (PGCs) are the progenitors of gametes (sperm and eggs), making them crucial for understanding germline transmission and epigenetic modifications, which are critical for studying transgenerational effects of nutrition and metabolic diseases. This is particularly relevant given the growing evidence that environmental factors, such as diet, can influence metabolic disease risk across generations through modulating epigenetic mechanisms, as seen in both human and animal studies. The unique biological and experimental attributes make PGCs in the chicken embryo a potential model for exploring the complex interactions between nutrition, epigenetic inheritance, and metabolic diseases, providing insights that are translatable to metabolic health and disease prevention tactics. This brief review emphasizes the potential of chicken PGCs as a model system to investigate the mechanisms underlying transgenerational metabolic programming.

Keywords:  PGCs; metabolic processes; nutriepigenetic; nutritional programming; transgenerational effects

DOI:  https://doi.org/10.3389/fcell.2025.1576768
bioRxiv. 2025 Apr 10. pii: 2025.04.09.647926. [Epub ahead of print]

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, Anthony L Schilmiller, Pablo E Visconti, Justin R Cross, Lonny R Levin, Jochen Buck, Melanie Balbach.

Prior to ejaculation, 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 13 C stable isotope labeling to follow glucose metabolism through sperm central carbon metabolic network before and after sperm activation. We identify regulatory steps which sperm use to alter their metabolic state from resting to highly active. In activated sperm, glucose flux through glycolysis is increased at the expense of the pentose phosphate pathway to increase energy yield. Increased glycolytic activity seems to be due to capacitation-induced stimulation of flux through aldolase. In the mitochondria-containing midpiece, glycolytically generated pyruvate feeds the TCA cycle to further maximize energy yield via oxidative phosphorylation. In the mitochondria-free principal piece of the tail, pyruvate produced from glycolysis is reduced to lactate by lactate dehydrogenase. Reduction to lactate regenerates oxidized 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 sperm.
Significance statement: A rapid switch from a quiescent to a high energy-demanding state during ejaculation is essential for sperm to reach and fertilize the oocyte. Somatic cells also undergo bioenergetic switches from low to very high energy demand. However, because metabolic processes essential for proliferation are going on in parallel, it is difficult to identify the molecular mechanisms regulating the increase in ATP production. This study represents the first complete picture of the metabolic reprogramming that happens in sperm upon ejaculation. Using stable isotope labeling, we identify rate-limiting enzymatic steps and points of regulation directing the changes in metabolic flux. Our sperm metabolic studies allow us to identify conserved mechanisms of metabolic regulation that are crucial for the survival of mammalian cells.

DOI: https://doi.org/10.1101/2025.04.09.647926