bims-ovagas 2026-04-26 papers

Cell Death Discov. 2026 Apr 20.

Zona pellucida is required for oocyte actin cortex and oocyte-somatic cell interactions during oocyte growth.

Shoujing Liang, Weixi Xiang, Ruping Quan, Jiayu Su, Chao Lv, Hualin Huang, Hongmei Xiao.

Structural defects in the zona pellucida (ZP), caused by mutations in ZP genes, are a recognized cause of female infertility; however, their pathogenic mechanisms are not fully understood. Here, we investigated how two distinct ZP defects (complete absence and thinning) compromise fertility using Zp1mut/mut and Zp2mut/mut rat models. We found that ZP deficiency leads to stage-specific oocyte loss during early antral follicle development in vivo and arrests the maturation of fully grown oocytes in vitro, which also exhibit reduced diameter and mitochondrial dysfunction. From the secondary follicle stage onward, granulosa cells showed reduced proliferation, increased apoptosis, and impaired adhesion, culminating in a disorganized cumulus-oocyte complex morphology and disrupted steroidogenesis by the antral stage. Further analysis revealed that the specialized structures for oocyte-somatic cell interaction, namely transzonal projections and oocyte microvilli, were disorganized and reduced in number. This structural disruption was accompanied by a global perturbation of the bidirectional communication and physical adhesion network between the oocyte and its somatic niche, underscoring the ZP's essential role in organizing this functional microenvironment. At the molecular level, single-cell transcriptomic and protein analyses demonstrated that ZP deficiency induces a thinning of the oocyte cortical actin layer and dysregulation of cytoskeletal dynamics. This was associated with an upregulation of actin-regulating proteins, including TPM4 and ACTN1, and the engagement of focal adhesion-related pathways. The observed cortical actin disorganization provides a plausible mechanistic link to the concurrent abnormalities in microvilli and cell-cell adhesion. Collectively, our results establish the ZP as a critical structural scaffold that ensures oocyte cortical integrity and coordinates the surrounding somatic cell niche. Its disruption leads to a progressive failure in oocyte-somatic cell interaction and support, ultimately resulting in oocyte developmental impairment and loss. This study provides detailed mechanistic insights into the pathogenesis of ZP-related female infertility (particularly empty follicle syndrome).

DOI: https://doi.org/10.1038/s41420-026-03124-9

EMBO J. 2026 Apr 21.

Dynamic blebbing and absence of organelle transfer during mouse oocyte formation.

Eishi Aizawa, So Shimamoto, Eriko Kajikawa, Junko Hara, Takaya Abe, Hiroki Shibuya, Tomoya S Kitajima.

Oocyte formation in mammals is a tightly regulated process essential for female fertility, yet the underlying mechanisms remain poorly understood. In this study, we establish an ex vivo culture system that faithfully recapitulates in vivo development and enables long-term live imaging of mouse fetal ovaries. Using high resolution imaging, we capture the dynamic behaviors of germ cells during the development from oogonia to nascent oocytes. We identify pronounced blebbing activity during the mitosis-to-meiosis transition. This behavior is regulated by meiotic initiation signals, underscoring its potential developmental relevance, although its precise role remains unclear. A prevailing model suggests that oocyte formation involves organelle transfer from neighboring germ cells during cyst breakdown. However, through photoconversion-based tracking, we observe no detectable transfer of mitochondria or centrosomes, as organelles remain confined to individual cells. These findings point to alternative mechanisms for cytoplasmic enrichment in oocytes. Our study provides new insights into mammalian oocyte formation and establishes a powerful platform for analyzing germ cell dynamics in real time.

DOI: https://doi.org/10.1038/s44318-026-00780-6

Aging Cell. 2026 May;25(5): e70506

Age-Dependent Alterations of Chromosomal Passenger Complex Members During Implantation and Decidualization in the Mouse Uterus.

Ezgi Golal, Cemre Nur Balci, Nuray Acar.

Successful embryo development, acquisition of uterine receptivity, implantation, and decidualization during the peri-implantation window are essential events that ensure a healthy pregnancy. While ovarian aging has long been considered the primary cause of age-related decline in fertility, emerging evidence demonstrates that uterine aging also compromises the ability to support pregnancy. The chromosomal passenger complex, composed of pIncenp, Aurora B, Survivin, and Borealin, is a critical regulator of cell cycle progression, particularly in chromosome condensation, mitotic spindle organization, and cytokinesis. We investigated age-associated changes in the expression and localization of those members, as well as the proliferation marker Ki-67, at implantation sites in mice during the peri-implantation period. Female mice aged 12, 20, and 26-32 weeks were used, and uterine tissues were collected on Days 5, 6, and 8 of pregnancy. Immunohistochemistry was performed to determine the localization of those proteins and Ki-67, while Western blotting was used to quantify protein expression levels. Our results revealed dynamic and age-dependent alterations in protein expression throughout pregnancy. Ki-67 expression decreased with advancing age in the luminal and glandular epithelium on Day 5, whereas pIncenp and Survivin levels were elevated in the stromal compartment of older mice. On Day 6, pIncenp, Borealin, and Survivin expression increased in the luminal epithelium of aging groups, and Aurora B expression was higher in older mice on Day 8. These findings highlight a potential role for complex dysregulation in impaired implantation/decidualization with maternal aging and may provide insight into mechanisms underlying implantation failure and recurrent pregnancy loss.

Keywords: Aurora B; Borealin; Ki‐67; Survivin; aging; implantation; mouse; pIncenp

DOI: https://doi.org/10.1111/acel.70506

Hum Reprod. 2026 Apr 19. pii: deag061. [Epub ahead of print]

Large-scale analysis of FMR1 CGG repeat length and risk of premature ovarian insufficiency in over 92 000 women.

Emily J Morbey, Felix R Day, Daniel J Wright, Jack R A Murzynowski, Sinead M McGlacken-Byrne, Anna Murray, Ken K Ong, John R B Perry.

STUDY QUESTION: Does FMR1 repeat length confer clinically meaningful predictive value for premature ovarian insufficiency (POI)?
SUMMARY ANSWER: FMR1 repeat length increases POI risk from ∼36 repeats onward but has limited diagnostic utility compared with a polygenic score for menopause timing.
WHAT IS KNOWN ALREADY: FMR1 premutation carriers (≥55 repeats) are reported to have high risk of Fragile-X Associated Primary Ovarian Insufficiency (FXPOI), but prior studies were small and highly ascertained.
STUDY DESIGN, SIZE, DURATION: Cross-sectional analysis of ∼92 000 women from the UK Biobank with genetic and health data.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Female UK Biobank participants were genotyped for FMR1 repeat length. Associations with self-reported POI, age at menopause, and other reproductive phenotypes were analysed in women. FMR1 protein levels were measured, and genome-wide analyses were conducted to identify potential genetic modifiers.
MAIN RESULTS AND THE ROLE OF CHANCE: Of 518 female premutation carriers with available age at natural menopause, only 6.9% reported POI. Elevated POI risk was observed starting at 36 repeats, increasing continuously with repeat length, but no threshold showed strong predictive power (maximum AUC 0.60 vs AUC 0.64 for polygenic score). No association was found between repeat length and FMR1 protein levels, consistent with an RNA gain-of-function toxicity mechanism. RAD52 was identified as a potential genetic modifier.
LARGE SCALE DATA: UK Biobank resource (https://www.ukbiobank.ac.uk).
LIMITATIONS, REASONS FOR CAUTION: POI was self-reported rather than clinically confirmed. Analyses could not assess AGG interruptions, mosaicism, or X-inactivation. Genetic modifiers require replication. Findings are limited to a single population dataset.
WIDER IMPLICATIONS OF THE FINDINGS: These results challenge the utility of the FXPOI disease category, suggest limited diagnostic value of clinical FMR1 premutation testing for POI, and highlight alternative mechanisms and potential modifiers such as RAD52.
STUDY FUNDING/COMPETING INTEREST(S): This work was conducted using the UK Biobank resource (application 9905). This work was funded by the Medical Research Council (unit programs: MC_UU_12015/2, MC_UU_00006/2) and Wellcome (Discovery award 302536/Z/23/Z). The sponsors had no role in the study design, collection, analysis, or interpretation of the data, the writing of the manuscript or the decision to submit it for publication. J.R.B.P. and A.M. have engaged in paid consultancy for Ovartix Ltd.
TRIAL REGISTRATION NUMBER: N/A.

Keywords: FMR1 ; fragile X-associated primary ovarian insufficiency; menopause; premature ovarian insufficiency; whole genome sequencing

DOI: https://doi.org/10.1093/humrep/deag061

Reprod Biol. 2026 Apr 21. pii: S1642-431X(26)00039-2. [Epub ahead of print]26(3): 101217

Organoids in polycystic ovary syndrome: Emerging platforms and future directions.

Ishanka Singh, Anuja Pant, Pawan Kumar Maurya.

Polycystic ovary syndrome (PCOS) is a prevalent and heterogeneous endocrine disorder affecting women of reproductive age, characterized by hyperandrogenism, ovulatory dysfunction, polycystic ovarian morphology, and metabolic disturbances, including insulin resistance. Despite its high global burden, mechanistic understanding remains incomplete due to limitations of conventional animal models and two-dimensional cultures, which fail to recapitulate the structural organization, endocrine dynamics, and patient-specific variability of human reproductive tissues. Organoid technology has emerged as a transformative platform to bridge this gap. Derived from adult stem cells or pluripotent stem cells, including induced pluripotent stem cells, ovarian and endometrial organoids self-organize into three-dimensional architectures that preserve cellular heterogeneity, hormone responsiveness, and disease-relevant molecular signatures. These systems reproduce key features of PCOS, such as dysregulated steroidogenesis, impaired granulosa-theca cell communication, follicular arrest, progesterone resistance, and oxidative stress-associated dysfunction. Patient-derived organoids further enable investigation of inter-individual heterogeneity and provide platforms for personalized drug testing and biomarker discovery. Integration with bioengineered scaffolds and microfluidic organ-on-chip systems extends modeling capacity to dynamic endocrine feedback and multi-organ interactions, enhancing physiological relevance. Although current organoid platforms do not fully capture systemic neuroendocrine and metabolic complexity, they offer powerful complementary tools for mechanistic interrogation. Collectively, organoid-based approaches redefine experimental modeling in PCOS by linking human-specific tissue biology with translational applications, thereby advancing precision diagnostics and individualized therapeutic strategies.

Keywords: Organoids; Ovary; Polycystic ovary syndrome (PCOS); Precision medicine; Reproductive biology

DOI: https://doi.org/10.1016/j.repbio.2026.101217

Cell Death Discov. 2026 Apr 19.

Silencing of METTL16 protects granulosa cells from the cisplatin-induced ferroptosis in premature ovarian failure.

Jing Xiong, Ling He, Yongjing Zhang, Lifang Li.

Premature ovarian failure (POF) and insufficiency induced by cisplatin are common complications associated with gynecological diseases. This study aims to investigate the role of N6-methyladenosine (m6A) methyltransferase METTL16 in cisplatin-induced ovarian granulosa cells ferroptosis. In cisplatin-treated ovarian tissue, the level of METTL16 was significantly elevated. Furthermore, METTL16 was also upregulated in cisplatin-stimulated granulosa cells. Functionally, silencing METTL16 inhibited iron accumulation and lipid peroxidation, while alleviating mitochondrial injury. Mechanistically, METTL16 was found to target NRF2, negatively regulating its RNA stability, and YTHDF2 facilitated the degradation of NRF2 mRNA. In summary, the METTL16/YTHDF2/NRF2 axis regulates ferroptosis in cisplatin-stimulated granulosa cells in POF. This study suggests that METTL16 may serve as a promising immunotherapeutic target for POF.

DOI: https://doi.org/10.1038/s41420-026-03081-3