bims-cebooc 2025-09-14 papers

bims-cebooc

Biomed News

on Cell biology of oocytes

Issue of 2025–09–14
twelve papers selected by
Gabriele Zaffagnini, Universität zu Köln

Decoding zebrafish oogenesis: From primordial germ cell development to fertilization.
Abundance of Maternal Mitochondrial Genome Is Dispensable up to the Mitochondrial Genome Activation in Post-Implantation Embryos.
A snapshot of proteostasis in human oocytes.
Intrauterine hyperglycemia impairs mouse primordial germ cell development and fertility by sex-specific epigenetic reprogramming interference.
Emerging principles and models of human primordial germ cell development.
Abnormal zona pellucida and follicular development in ZP1-mutant macaques.
Modeling and Validation of Oocyte Mechanical Behavior Using AFM Measurement and Multiphysics Simulation.
Advances in ovarian follicle culture systems: exploring the interplay between cells, matrix, and ovarian architecture.
Female membrane proteins regulate postmating ovulation in Drosophila melanogaster by ovulin-dependent and -independent pathways.
Frozen potential: embryo research at the crossroads of ethics, regulation and scientific opportunity.
Protocol for imaging and quantifying single-cell CDK activity levels during early mouse embryonic development by time-lapse microscopy.
Slowing down the clock on ovarian aging-does the ovary hold the secret to the fountain of youth?

Semin Cell Dev Biol. 2025 Sep 05. pii: S1084-9521(25)00060-6. [Epub ahead of print]175 103650

Decoding zebrafish oogenesis: From primordial germ cell development to fertilization.

Laura Hofmann, Carl-Philipp Heisenberg.

  Oogenesis - the formation and development of an oocyte - is fundamental to reproduction and embryonic development. Due to its accessibility to genetic manipulations and the ability to culture and experimentally manipulate oocytes ex vivo, zebrafish has emerged as a powerful vertebrate model system for studying oogenesis. In this review, we provide a comprehensive overview of zebrafish oogenesis, from early germ cell formation to oocyte maturation and fertilization. We discuss recent advances in uncovering the molecular and cellular mechanisms driving this complex process and highlight key knowledge gaps that remain to be addressed.

Keywords:  Oogenesis; Zebrafish

DOI:  https://doi.org/10.1016/j.semcdb.2025.103650
FASEB J. 2025 Sep 15. 39(17): e70986

Abundance of Maternal Mitochondrial Genome Is Dispensable up to the Mitochondrial Genome Activation in Post-Implantation Embryos.

Miki Shavit, Marie Vancová, Jan Jedlicka, Tomáš Bílý, Mushrek Mahrouk, Jan Cendelin, Kateřina Grygarova, Kristýna Popelková, Zdeněk Tůma, Gabriela Pribanova, Jitka Kuncová, Jan Nevoral.

  Mitochondria in the egg are suggested to be crucial for the onset of new life. However, there is ambiguous knowledge about the necessity for fertilization and early embryonic development. Therefore, we created a conditional Tfam knockout (TfamloxP/loxP; Zp3-Cre) to produce Tfamnull oocytes for investigation of the mitochondrial abundance in oocytes and early embryos. This created mtDNA-depleted eggs, although the abundance of mitochondria did not change. Despite decreased mitochondrial membrane potential, Tfamnull oocytes matured and were fertilized, which led to embryo formation. These Tfamnull eggs were developed into mtDNA-deficient blastocysts. Both TFAM and mtDNA appear to be dispensable for the success of embryo implantation. Tfam expression and mtDNA replication rescue the mtDNA-deficient embryo after implantation, enabling passage through a post-implantation bottleneck, and allowing survivor embryos to develop into healthy individuals. Our findings highlight the uncoupled relationship between mtDNA replication and mitochondrial abundance in the growing oocyte and show the importance of the oocyte bulk mtDNA for successful mitochondrial activation in post-implantation embryos.

Keywords:  embryo; fertilization; mitochondrial; mitochondrion; oocyte; transcription factor A

DOI:  https://doi.org/10.1096/fj.202501179R
Nat Struct Mol Biol. 2025 Sep 09.

A snapshot of proteostasis in human oocytes.

Dimitris Typas.

DOI: https://doi.org/10.1038/s41594-025-01679-2
Cell Discov. 2025 Sep 09. 11(1): 74

Intrauterine hyperglycemia impairs mouse primordial germ cell development and fertility by sex-specific epigenetic reprogramming interference.

Jiangshan Cong, Qing Li, Yangyang Li, Minghao Li, Yan Shi, Peiran Hu, Xidi Yin, Qianyun Zhang, Jianzhong Sheng, Jinsong Li, Guolian Ding, Yu Zhang, Hefeng Huang.

Adverse intrauterine environments, such as hyperglycemia, impair sexual reproduction and species continuity, yet the underlying mechanisms remain poorly understood. In this study, we demonstrated that intrauterine hyperglycemia significantly disrupted primordial germ cell (PGC) development, especially in female offspring, thus reducing fertility. Using Oct4-EGFP transgenic mice with intrauterine hyperglycemia exposure, we revealed that hyperglycemia compromised sexually specific chromatin accessibility and DNA methylation reprogramming during PGC development. Particularly, in female PGCs, hyperglycemia leads to the aberrant retention of chromatin accessibility at pluripotency gene promoters such as Nanog and Tfap2c, inhibiting proper gene silencing and blocking the initiation of meiosis, which ultimately hinders oocyte maturation. Conversely, male PGCs exhibit less severe changes in chromatin accessibility and gene transcription. Intriguingly, the global DNA methylation reconstruction is impaired in male PGCs, particularly in key imprinted gene regions, suggesting potential developmental ramifications for later stages and even subsequent generations. Particularly, our findings indicate that intrauterine hyperglycemia adversely affects sex differentiation in PGCs by disrupting the expression of critical sex-determining transcription factors. Collectively, these findings highlight how intrauterine hyperglycemia interferes with sex-specific epigenetic reprogramming during PGC development, leading to abnormal germ cell development, reduced fertility, and adverse intergenerational effects.

DOI: https://doi.org/10.1038/s41421-025-00821-0
Development. 2025 Sep 01. pii: dev204968. [Epub ahead of print]152(17):

Emerging principles and models of human primordial germ cell development.

Navin B Ramakrishna, João Pedro Alves-Lopes, Wolfram H Gruhn.

  In humans, primordial germ cells (hPGCs) are the earliest precursors committed to forming sperm or egg. During the first trimester of embryonic development, hPGCs undergo extensive epigenetic reprogramming and are subject to fitness selection, laying the foundation for future gametogenesis and normal embryonic development. During these processes, hPGCs interact with dynamic microenvironments that remain incompletely understood. Recent advances in transcriptomic and epigenetic profiling have revealed signalling cues and regulatory mechanisms governing hPGC development in human embryos, complemented by insights from non-human primate models. In parallel, pluripotent stem cell-based systems that model hPGC differentiation have emerged in the past decade as valuable platforms for mechanistic studies and form the basis of ongoing efforts to establish human in vitro gametogenesis. In this Review, we discuss the microenvironmental and epigenetic changes accompanying hPGC specification, migration and gonadal development up to week 10 of embryogenesis. Building on these insights, we examine current model systems for recapitulating hPGC development, and highlight the mechanistic understandings they have enabled.

Keywords:   In vitro gametogenesis; Epigenetics; Human primordial germ cells; Microenvironment; Pluripotency; Stem cell models

DOI:  https://doi.org/10.1242/dev.204968
Zool Res. 2025 Sep 18. pii: 2095-8137(2025)05-1093-15. [Epub ahead of print]46(5): 1093-1107

Abnormal zona pellucida and follicular development in ZP1-mutant macaques.

Wei Meng, Bao-Zhen Liu, Dan Huang, Yu-Tao Fan, Cheng-Gang Xiong, Ying-Ting Zhang, Lei-Lei Zhao, Yong-Long Guo, Mu-Hua Lai, Xin-Yuan Zhao, Ya-Qing Li, Shi-Kun Zhao, Jing-Tao Zeng, Chuan-He Liu, Ji-Long Liu, Chen-Hui Ding, Shi-Hua Yang.

  Zona pellucida glycoprotein-1 (ZP1) is essential for maintaining oocyte structural integrity and facilitating fertilization. Mutations in ZP1 are strongly associated with primary infertility disorders such as fertilization failure and empty follicle syndrome; however, the absence of accurate experimental models has hindered mechanistic understanding and obscured the etiological basis of ZP1-related infertility. In this study, CRISPR/Cas9-mediated genome editing was employed to generate two ZP1-edited cynomolgus macaques ( Macaca fascicularis), designated #ZP1-1 (male) and #ZP1-2 (female). Following sexual maturation, oocytes retrieved from #ZP1-2 through superovulation exhibited a marked increase in zona pellucida-deficient oocytes and a significant reduction in maturation rates compared to controls. Integrated analyses, including immunofluorescence staining, transmission electron microscopy, transcriptomic profiling of oocytes, and histopathological examination of ovarian tissue, revealed disrupted folliculogenesis and oocyte anomalies consistent with phenotypes observed in human empty follicle syndrome. These findings establish the ZP1-knockout cynomolgus macaque as the first non-human primate model of ZP1-related infertility, providing a valuable platform for elucidating disease mechanisms and informing the development of targeted interventions for infertility arising from ZP gene mutations.

Keywords:  Cynomolgus macaques; Infertility; ZP1; Zona pellucida

DOI:  https://doi.org/10.24272/j.issn.2095-8137.2024.415
Sensors (Basel). 2025 Sep 03. pii: 5479. [Epub ahead of print]25(17):

Modeling and Validation of Oocyte Mechanical Behavior Using AFM Measurement and Multiphysics Simulation.

Yue Du, Yu Cai, Zhanli Yang, Ke Gao, Mingzhu Sun, Xin Zhao.

  Mechanical models are capable of simulating the deformation and stress distribution of oocytes under external forces, thereby providing insights into the underlying mechanisms of intracellular mechanical responses. Interactions with micromanipulation tools involve forces like compression and punction, which are effectively analyzed using principles of solid mechanics. Alternatively, fluid-structure interactions, such as shear stress at fluid junctions or pressure gradients within microchannels, are best described by a multiphase flow model. Developing the two models instead of a single comprehensive model is necessary due to the distinct nature of cell-tool interactions and cell-fluid interactions. In this study, we developed a finite element (FE) model of porcine oocytes that accounts for the viscoelastic properties of the zona pellucida (ZP) and cytoplasm for the case when the oocytes interacted with a micromanipulation tool. Atomic force microscopy (AFM) was employed to measure the Young's modulus and creep behavior of these subcellular components that were incorporated into the FE model. When the oocyte was solely interacting with the fluids, we simulated oocyte deformation in microfluidic channels by modeling the oocyte-culture-medium system as a three-phase flow, considering the non-Newtonian behavior of the oocyte's components. Our results show that the Young's modulus of the ZP and cytoplasm were determined to be 7 kPa and 1.55 kPa, respectively, highlighting the differences in the mechanical properties between these subcomponents. Using the developed layered FE model, we accurately simulated oocyte deformation during their passage through a narrow-necked micropipette, with a deformation error of approximately 5.2% compared to experimental results. Using the three-phase flow model, we effectively simulated oocyte deformation in microfluidic channels under various pressures, validating the model's efficacy through close agreement with experimental observations. This work significantly contributes to assessing oocyte quality and serves as a valuable tool for advancing cell mechanics studies.

Keywords:  AFM; cell mechanical model; creep behavior; layered structure; three-phase flow model; viscoelastic properties

DOI:  https://doi.org/10.3390/s25175479
Anim Reprod. 2025 ;22(3): e20250066

Advances in ovarian follicle culture systems: exploring the interplay between cells, matrix, and ovarian architecture.

Alberto Maria Luciano, Noemi Monferini, Ludovica Donadini, Pritha Dey, Fernanda Fagali Franchi, Valentina Lodde, Federica Franciosi.

  The ability to develop oocytes from the earliest follicular stages through maturation and fertilization in vitro would revolutionize fertility preservation in human medicine and animal breeding. Instead, current assisted reproductive technologies rely only on a limited portion of the female gamete reserve, corresponding to the antral population, while the preantral follicle reserve remains unexploited, mainly due to a lack of knowledge regarding the mechanisms that guide preantral follicle differentiation and folliculogenesis in vitro. This review highlights the efforts made thus far and suggests an approach to studying the mechanisms and ovarian environment to enhance preantral follicle culture systems.

Keywords:  3D; culture system; ovary; preantral follicles; scaffold

DOI:  https://doi.org/10.1590/1984-3143-AR2025-0066
Proc Natl Acad Sci U S A. 2025 Sep 16. 122(37): e2508783122

Female membrane proteins regulate postmating ovulation in Drosophila melanogaster by ovulin-dependent and -independent pathways.

Mengye Yang, Melissa A White, Geoffrey D Findlay, Ryan C Vignogna, Jennifer Apger-McGlaughon, Nathan L Clark, Jae Young Choi, J Christopher Fromme, Mariana F Wolfner.

  Ovulation is an intricate process that is essential for reproductive success. In Drosophila melanogaster, ovulation increases after mating. This increase is initiated by the male seminal fluid protein ovulin and is executed by female pathways, including octopamine (OA) neuronal signaling. Despite OA signaling's central role in ovulation regulation, the broader molecular landscape underlying female control of ovulation remains poorly understood. Here, using ovulin as a probe, we performed evolutionary rate covariation and AlphaFold-Multimer prediction screens to identify candidate female ovulation-regulating proteins. Ovulation assays performed on knockdowns or mutants of identified membrane-protein candidates revealed seven important female ovulation regulators: Lgr3, GabaβR1, SIFaR, mthl9, Smog, Cirl, and CG6067. Lgr3 and GabaβR1 function in an ovulin-dependent manner, while SIFaR and mthl9 regulate ovulation independently of ovulin. For proteins with known nervous system expression, we examined their requirement in OA neurons and their expression in female reproductive tract neurons. Tissue-specific knockdown revealed that Lgr3, GabaβR1, SIFaR, and CG6067 act in OA neurons to influence ovulation, highlighting OA neurons as a key signaling hub. Additionally, Lgr3, GabaβR1, SIFaR, Smog, and Cirl are expressed in OA neurons innervating the reproductive tract, suggesting a potential local function. Finally, we identified evidence of recurrent positive selection having acted on residues within Smog's ligand binding region, which is interesting in light of ovulin's rapid evolution. Together, these findings significantly expand our understanding of the molecular networks regulating ovulation following mating in Drosophila.

Keywords:  Drosophila; membrane proteins; octopaminergic neurons; ovulation; ovulin

DOI:  https://doi.org/10.1073/pnas.2508783122
Development. 2025 09 01. pii: dev205133. [Epub ahead of print]152(17):

Frozen potential: embryo research at the crossroads of ethics, regulation and scientific opportunity.

Mina Popovic, Catello Scarica, Susana M Chuva de Sousa Lopes, Marta N Shahbazi.

  In an era of expanding reproductive possibilities, the human embryo has come to represent both immense potential and profound constraint. Advances in medically assisted reproduction (MAR) have led to the cryopreservation of hundreds of thousands of embryos each year, yet many remain unused and are ultimately discarded. Meanwhile, studies aimed at understanding infertility, early human development and preventing miscarriage continue to face significant barriers, with only a small fraction of embryos ever donated to research. This disconnect, shaped by regulatory ambiguity, raises a deeper question: is it more ethical to discard an embryo than to learn from it? This Perspective outlines the biological inefficiencies of human reproduction and the clinical imperative to improve MAR outcomes. We then examine the global patchwork of embryo research regulation by comparing national approaches. Drawing on examples from both clinical and research practice, we argue that permissiveness alone does not guarantee scientific progress, just as restriction does not ensure ethical integrity. A meaningful global conversation on embryo research must move beyond the binary of permissiveness versus prohibition, and toward frameworks that support responsible, transparent, and ethically grounded innovation.

Keywords:  Ethics; Human embryo; IVF; Infertility; Miscarriage

DOI:  https://doi.org/10.1242/dev.205133
STAR Protoc. 2025 Sep 08. pii: S2666-1667(25)00471-X. [Epub ahead of print]6(3): 104065

Protocol for imaging and quantifying single-cell CDK activity levels during early mouse embryonic development by time-lapse microscopy.

Bechara Saykali, Andy D Tran, Michael J Kruhlak, Sergio Ruiz.

  Tracking the translocation of fluorescent-based reporters at the single-cell level in living mouse embryos requires specialized expertise in mouse embryology and deep computational skills. Here, we detail an approach to quantify cyclin-dependent kinase (CDK) activity levels in single cells throughout different stages of the pre-implantation embryo. We discuss in vitro culture strategies that enable efficient live fluorescent confocal image acquisition and subsequent cell tracking. Finally, we describe the image analysis workflow needed for the processing and visualization of the datasets obtained. For complete details on the use and execution of this protocol, please refer to Saykali et al.1.

Keywords:  Bioinformatics; cell differentiation; developmental biology

DOI:  https://doi.org/10.1016/j.xpro.2025.104065
Geroscience. 2025 Sep 10.

Slowing down the clock on ovarian aging-does the ovary hold the secret to the fountain of youth?

Paula Benny, Xi Yuan, Qian Yang, Jorge Chavarro, Brian Kennedy, Zhongwei Huang.

  In the past century, the human Lifespan has doubled. However, this is not equivalent to Healthspan which refers to the number of years spent healthy and free from disease. Women have an additional level of complexity on the path to optimal healthspan where health resilience dramatically decreases following menopause and this is due to their ovaries aging by midlife. It still remains elusive on why and how the ovaries in women, albeit their distinct and vital reproductive functions, start to age before any other organs. Following menopause, women are at increased risks of age-associated chronic diseases such as cardiometabolic disease, osteoporosis, sarcopenia, frailty, and neurocognitive decline. By preserving reproductive longevity through targeting the ovary as the organ to rejuvenate in women, optimal healthspan could be obtained in women. Interestingly, population studies have shown that women who conceive naturally and give birth at advanced reproductive ages are demonstrated to have superior postmenopausal longevity. Correspondingly, men Lived longer with a sister reproducing after 45 years of age in natural fertility conditions, suggesting that late female fertility and slow somatic aging may be promoted by the same genetic variants. Causal inference analysis showed a link between increased reproductive lifespan (prolonged ovarian lifespan or later age at natural menopause) and a reduction of diseases such as diabetes and osteoporosis. Essentially, fewer ovarian follicles and shorter ovarian lifespan were associated with poorer health later in life. Therefore, innovative ways to understand and target the ovaries in women for gero-protection have the potential to avert aging diseases triggered by the female menopause. Our narrative review aims to integrate existing information from systemic and reproductive aging from preclinical and human studies to devise novel methodologies to avert ovarian aging which could potentially improve the health trajectory in aging women. Similar strategies can be applied to men to achieve healthy longevity in the population. While there are certain things one has little control over, such as genetics and the inevitable reduction of reproductive hormone levels over time, there are modifiable risk factors which can be targeted to preserve reproductive longevity by uniquely targeting the ovary especially in modifying and improving the ovarian microenvironment to ensure survival of the ovarian follicles which determine true reproductive lifespan and healthspan. This can be achieved by modifying diet, sleep patterns, and exercise and limiting toxin exposure to ensure optimal ovarian health, through healthy and functional ovarian follicles, which could bring us a step closer to enhancing women's healthspan and human longevity.

Keywords:  Aging; Ovarian biology; Quality of life; Reproductive longevity; Women’s health

DOI:  https://doi.org/10.1007/s11357-025-01876-3