bims-mazytr 2025-03-23 papers

bims-mazytr

Biomed News

on Maternal‐to‐zygotic transition

Issue of 2025–03–23
nine papers selected by
川一刀

Endosomal-lysosomal organellar assembly (ELYSA) structures coordinate lysosomal degradation systems through mammalian oocyte-to-embryo transition.
Mitofusin 1 Drives Preimplantation Development by Enhancing Chromatin Incorporation of Histone H3.3.
FSP1 regulates ferroptosis and mitochondrial function during mouse oocyte maturation.
Totipotency or plenipotency: rethinking stem cell bipotentiality.
Sperm activation for fertilization requires robust activity of the TAT-5 lipid flippase.
Polarization-independent regulation of the subcellular localization of Yes-associated protein 1 during preimplantation development.
Ultrastructural characteristics of bovine embryos produced in vitro and vitrified using the cryotop method.
Utilization of a 3D in vitro co-culture system to characterize embryonic mechanisms associated with implantation.
The nuclear exosome co-factor MTR4 shapes the transcriptome for meiotic initiation.

Elife. 2025 Mar 17. pii: RP99358. [Epub ahead of print]13

Endosomal-lysosomal organellar assembly (ELYSA) structures coordinate lysosomal degradation systems through mammalian oocyte-to-embryo transition.

Yuhkoh Satouh, Takaki Tatebe, Isei Tanida, Junji Yamaguchi, Yasuo Uchiyama, Ken Sato.

  Mouse oocytes undergo drastic changes in organellar composition and their activities during maturation from the germinal vesicle (GV) to metaphase II (MII) stage. After fertilization, the embryo degrades parts of the maternal components via lysosomal degradation systems, including autophagy and endocytosis, as zygotic gene expression begins during embryogenesis. Here, we demonstrate that endosomal-lysosomal organelles form large spherical assembly structures, termed endosomal-lysosomal organellar assemblies (ELYSAs), in mouse oocytes. ELYSAs are observed in GV oocytes, attaining sizes up to 7-8 μm in diameter in MII oocytes. ELYSAs comprise tubular-vesicular structures containing endosomes and lysosomes along with cytosolic components. Most ELYSAs are also positive for an autophagy regulator, LC3. These characteristics of ELYSA resemble those of ELVA (endolysosomal vesicular assemblies) identified independently. The signals of V1-subunit of vacuolar ATPase tends to be detected on the periphery of ELYSAs in MII oocytes. After fertilization, the localization of the V1-subunit on endosomes and lysosomes increase as ELYSAs gradually disassemble at the 2-cell stage, leading to further acidification of endosomal-lysosomal organelles. These findings suggest that the ELYSA/ELVA maintain endosomal-lysosomal activity in a static state in oocytes for timely activation during early development.

Keywords:  cell biology; developmental biology; endosome; lysosomal maturation; mouse; oocyte activation; oocyte dormancy; ubiquitination; vacuolar ATPase

DOI:  https://doi.org/10.7554/eLife.99358
Adv Sci (Weinh). 2025 Mar 16. e2414985

Mitofusin 1 Drives Preimplantation Development by Enhancing Chromatin Incorporation of Histone H3.3.

Xiao-Yan Shi, Yu Tian, Yu-Fan Wang, Yi-Ran Zhang, Ying Yin, Qing Tian, Lei Li, Bing-Xin Ma, Ximiao He, Li-Quan Zhou.

  Mitofusin 1 (MFN1) plays a crucial role in mitochondrial fusion and oocyte development. However, its function in preimplantation embryonic development and its potential involvement in epigenetic regulation remain poorly understood. In this study, it is shown that MFN1 interacts with PADI6, a key component of the cytoplasmic lattice in oocytes and early embryos. MFN1 deficiency in mice results in reduced PADI6 levels and decreased expression of translational machinery components, which suppress protein synthesis activity and lower histone H3.3 abundance. These disruptions lead to the failure of male pronucleus formation, aberrant zygotic genome activation, and impaired embryonic development. It is further demonstrated that the MFN1 activator S89 promotes H3.3 incorporation and rescues early development in maternally aged embryos with low MFN1 levels. Additionally, a positive correlation between MFN1 and H3.3 protein levels in early human embryos is observed. Together, these findings provide new insights into MFN1's role in regulating epigenetic reprogramming during preimplantation embryo development.

Keywords:  H3.3; MFN1; cytoplasmic lattice; preimplantation; zygotic genome activation

DOI:  https://doi.org/10.1002/advs.202414985
Exp Cell Res. 2025 Mar 18. pii: S0014-4827(25)00120-X. [Epub ahead of print]447(2): 114524

FSP1 regulates ferroptosis and mitochondrial function during mouse oocyte maturation.

Hongzhen Ruan, Huifen Xiang, Yajing Liu, Peiwen Wang, Liuliu Dong, Yunxia Cao, Dan Liang, Zhiming Ding.

  Oocyte quality plays a fundamental role in fertilization and embryonic development. Emerging evidence indicates that ferroptosis may impair oocyte quality. Ferroptosis suppressor protein 1 (FSP1), a known ferroptosis inhibitor, has an uncharacterized function in regulating oocyte quality during meiotic maturation. This study identified FSP1 expression across all stages of meiotic maturation with localization to the cytoplasm of mouse oocytes. Aged mice exhibited a marked reduction in FSP1 expression within the ovaries and oocytes. Pharmacological inhibition of FSP1 disrupted germinal vesicle breakdown and polar body emission, leading to spindle defects and chromosome misalignment. Additionally, FSP1 inhibition persistently activated the spindle assembly checkpoint, resulting in meiotic arrest. At the mechanistic level, inhibition of FSP1 led to an increase in intracellular Fe2+ levels, enhanced dihydroethidium fluorescence, excessive accumulation of reactive oxygen species, and intensified lipid peroxidation. Disruptions in ferroptosis-associated gene expression further indicated that oocytes underwent ferroptosis. Moreover, mitochondrial dysfunction was evident following FSP1 inhibition, as reflected by aberrant mitochondrial distribution, diminished ATP production, and an elevated mitochondrial membrane potential. Collectively, these results establish FSP1 as a key regulator of oocyte meiotic maturation by modulating iron homeostasis and mitochondrial function, while its inhibition triggers ferroptosis-dependent meiotic failure.

Keywords:  FSP1; Ferroptosis; Meiosis; Mitochondria; Oocyte

DOI:  https://doi.org/10.1016/j.yexcr.2025.114524
Curr Opin Genet Dev. 2025 Mar 18. pii: S0959-437X(25)00034-6. [Epub ahead of print]92 102342

Totipotency or plenipotency: rethinking stem cell bipotentiality.

Duancheng Wen, Jianlong Wang.

The term 'totipotency' has often been misapplied in stem cell research to describe cells with embryonic and extraembryonic bipotentiality, despite a lack of evidence that they can generate an entire organism from a single cell. Additionally, no specific term currently distinguishes bipotential stem cells from pluripotent cells, which contribute poorly to extraembryonic tissues. This review examines the developmental continuum from totipotency to pluripotency in early embryos and revisits the previously proposed concept of plenipotency in preimplantation development. We evaluate emerging stem cell models that exhibit bipotentiality but have lost the ability to autonomously initiate and sustain the sequential fate decisions necessary to develop into a complete organism. Unlike totipotent embryonic cells, which retain the information required to initiate fate decisions at the correct timing and cell numbers, these stem cells have lost that capacity. This loss of critical developmental information distinguishes totipotency from plenipotency, with bipotential stem cells aligning more closely with the latter. By distinguishing plenipotency from totipotency and pluripotency, we aim to refine terminology, enhance our understanding of early embryonic development, and address ethical considerations in human research.

DOI: https://doi.org/10.1016/j.gde.2025.102342
bioRxiv. 2025 Mar 06. pii: 2025.03.06.641851. [Epub ahead of print]

Sperm activation for fertilization requires robust activity of the TAT-5 lipid flippase.

Katherine A Maniates, Saai Suryanarayanan, Alissa Rumin, Morgan Lewin, Andrew Singson, Ann M Wehman.

During fertilization, sperm and egg membranes signal and fuse to form a zygote and begin embryonic development. Here, we investigated the role of lipid asymmetry in gametogenesis, fertilization, and embryogenesis. We find that phosphatidylethanolamine asymmetry is lost during meiosis prior to phosphatidylserine exposure. We show that TAT-5, the P4-ATPase that maintains phosphatidylethanolamine asymmetry, is required for both oocyte formation and sperm activation, albeit at different levels of flippase activity. Loss of TAT-5 significantly decreases fertility in both males and hermaphrodites and decreases sperm activation. TAT-5 localizes to the plasma membrane of primary spermatocytes but is sorted away from maturing spermatids during meiosis. Our findings demonstrate that phosphatidylethanolamine asymmetry plays key roles during gametogenesis and sperm activation, expanding the roles of lipid dynamics in developmental cell fusion.

DOI: https://doi.org/10.1101/2025.03.06.641851
J Biol Chem. 2025 Mar 19. pii: S0021-9258(25)00278-9. [Epub ahead of print] 108429

Polarization-independent regulation of the subcellular localization of Yes-associated protein 1 during preimplantation development.

Shun Saito, Koji Nishiyama, Hanako Bai, Masashi Takahashi, Manabu Kawahara.

  Cell polarization is a crucial developmental process that determines cell differentiation in mouse embryos. During this process, an extensively expressed transcriptional regulator, Yes-associated protein 1 (YAP1), is localized either to the cytoplasm or nucleus via HIPPO signaling. In mouse pre-morula embryos, YAP1 is present in the nuclei of all cells. Thereafter, YAP1 is distributed to the nuclei of outer cells or cytoplasm of inner cells, depending on the establishment of cell polarity and morula formation. However, the dynamics of YAP1 localization in other species, including ruminants, remain unclear. To gain an in-depth understanding of cell differentiation in mammalian embryos, we investigated YAP1 localization changes in bovine embryos. Unlike in mouse morulae, YAP1 displayed cytoplasmic localization in most cells, including the outer cells of bovine morulae, after the 32-cell stage. Next, we analyzed the relationship between cell polarity and nuclear localization of YAP1. Polarization of outer cells in the bovine morula began at the late 16-cell stage and was established by the late 32-cell stage, indicating that polarization preceded the nuclear localization of YAP1 in bovine embryos. To explore the regulation of YAP1 localization in bovine morula, we analyzed zona-free embryos and found that the presence of the zona pellucida significantly enhanced YAP1 cytoplasmic localization. Moreover, we observed ectopic expression of SOX2 in zona-free blastocysts, which indicated that cytoplasmic localization of YAP1 was associated with the suppression of pluripotency in the trophectoderm. These findings provide valuable insights into the molecular mechanisms underlying the first cell differentiation in mammalian embryos.

Keywords:  Hippo pathway; Yes-associated protein 1 (YAP1); cattle; cell differentiation; cell polarity; morula; preimplantation; zona pellucida

DOI:  https://doi.org/10.1016/j.jbc.2025.108429
Cryo Letters. 2025 Jan-Feb;46(1):46(1): 57-66

Ultrastructural characteristics of bovine embryos produced in vitro and vitrified using the cryotop method.

J A Leite de Oliveira Cruz, R Artur da Silva Junior, R Desenzi, A Fernandes de Souza, M A Matos Donato, C C Bartolomeu, A M Batista.

BACKGROUND: Despite advancements in bovine embryos cryopreservation techniques, challenges remain, warranting further investigation into their impact on embryo morphology and viability so that outcomes can be improved.
OBJECTIVE: To analyze, through transmission electron microscopy (TEM), in vitro-produced bovine embryos vitrified using the Cryotop method.
MATERIALS AND METHODS: Groups of embryos were transferred to a stabilization solution (SS) containing 7.5% EG, 7.5% DMSO in maintenance medium (TCM-199 supplemented with 20% FBS) for 2 min, and then transferred to a vitrification solution (VS) containing 15% EG, 15% DMSO, and 0.5 M sucrose in maintenance medium. Warming was performed in five stages with decreasing concentrations of sucrose. After warming, the blastocysts were cultured for 24 h for subsequent survival analysis and ultrastructural evaluation. In vitro-produced bovine embryos that did not undergo the vitrification process were used as a fresh control.
RESULTS: Blastocoel reestablishment was observed in 52.3% (66/126) of vitrified embryos 24 h after warming, demonstrating the method's effectiveness in post-cryopreservation survival. Ultrastructural analysis of embryos from the fresh control group showed flattened trophoectodermal cells with prominent nuclei, well-preserved mitochondria, and Golgi complexes were also evident. Microvilli were observed in some regions near the zona pellucida. Embryos vitrified using the Cryotop method exhibited lesions consistent with the cryopreservation process, such as intracellular disorganization, mitochondrial injuries, and dispersion of microvilli.
CONCLUSIONS: Ultrastructural evaluation of in vitro-produced bovine embryos vitrified using the Cryotop method is an effective tool for increased understanding of the injuries caused to embryonic cells during the cryopreservation process. https://doi.org/10.54680/fr25110110612.
F S Sci. 2025 Mar 19. pii: S2666-335X(25)00022-9. [Epub ahead of print]

Utilization of a 3D in vitro co-culture system to characterize embryonic mechanisms associated with implantation.

Keelee J McCarty, Blair McCallie, William B Schoolcraft, Mandy Katz-Jaffe.

   OBJECTIVE: Implantation success is dependent on timely molecular signaling to establish embryonic apposition, adhesion and invasion. In an effort to elucidate this critical period in human reproduction, the objective of this study was to utilize a novel, time-lapse 3D in vitro co-culture system to characterize the timing of blastocyst development on the initial stages of implantation.
DESIGN: Endometrial biopsies were collected from fertile oocyte donors to generate individual 3D wells of separated monolayers of luminal endometrial epithelial and stromal cells for co-culture with an individual blastocyst (n = 72; maternal age = 36.3±5.1 years). Following 72h of co-culture (CytoSMART Lux3 time-lapse imaging system), blastocysts were evaluated for stage of implantation and separated into two groups: No Implantation (no adhesion or invasion) and Implantation (complete adhesion and invasion).
SUBJECTS: N/A Intervention (for RCT) or Exposure (for observational studies): N/A MAIN OUTCOME MEASURES: Immunohistochemistry and targeted qPCR gene expression were performed on individual blastocysts and on exosome purified small RNAs derived from supernatant.
RESULTS: Following successful implantation into the endometrial epithelium, correctly timed blastocysts experienced greater duration of apposition and adhesion, delayed onset of invasion, and increased number of spontaneous blastocyst collapse compared to slower developing blastocysts. Additionally, targeted gene expression analysis revealed an upward trend of implantation promoting genes GATA3, OCT4, and cell death regulatory gene CASP3 in correctly timed compared to slower developing blastocysts. Interestingly, as blastocysts became more attached to the epithelium, a downward trend of developmental genes CDX2 and BMP15 was observed. A downward trend of hsa-miR-1-3p and upward trend of hsa-miR-34b-5p was observed in the supernatant of co-cultured blastocysts that achieved successful implantation in co-culture. Top KEGG pathways impacted by these microRNA's were axon guidance, ubiquitin mediated proteolysis, and neurotrophin signaling pathway.
CONCLUSION: Time-lapse 3D in vitro co-culture revealed that the timing of blastocyst development is critical to the initial stages of implantation. The ability of the trophectoderm to expand, orient and initiate apposition may contribute to the higher likelihood of success as indicated by altered gene expression and regulatory pathways.

Keywords:  Implantation failure; blastocyst; co-culture; implantation potential

DOI:  https://doi.org/10.1016/j.xfss.2025.03.001
Nat Commun. 2025 Mar 17. 16(1): 2605

The nuclear exosome co-factor MTR4 shapes the transcriptome for meiotic initiation.

Li Zhang, Jianshu Wang, Zhidong Tang, Zhen Lin, Ruibao Su, Naijing Hu, Yao Tang, Gaoxiang Ge, Jing Fan, Ming-Han Tong, Yuanchao Xue, Yu Zhou, Hong Cheng.

Nuclear RNA decay has emerged as a mechanism for post-transcriptional gene regulation in cultured cells. However, whether this process occurs in animals and holds biological relevance remains largely unexplored. Here, we demonstrate that MTR4, the central cofactor of the nuclear RNA exosome, is essential for embryogenesis and spermatogenesis. Embryonic development of Mtr4 knockout mice arrests at 6.5 day. Germ cell-specific knockout of Mtr4 results in male infertility with a specific and severe defect in meiotic initiation. During the pre-meiotic stage, MTR4/exosome represses meiotic genes, which are typically shorter in size and possess fewer introns, through RNA degradation. Concurrently, it ensures the expression of mitotic genes generally exhibiting the opposite features. Consistent with these regulation rules, mature replication-dependent histone mRNAs and polyadenylated retrotransposon RNAs were identified as MTR4/exosome targets in germ cells. In addition, MTR4 regulates alternative splicing of many meiotic genes. Together, our work underscores the importance of nuclear RNA degradation in regulating germline transcriptome, ensuring the appropriate gene expression program for the transition from mitosis to meiosis during spermatogenesis.

DOI: https://doi.org/10.1038/s41467-025-57898-0