bims-cebooc Biomed News
on Cell biology of oocytes
Issue of 2024–06–30
ten papers selected by
Gabriele Zaffagnini, Centre for Genomic Regulation
  1. The impact of offspring and maternal obesogenic diets on adult offspring oocyte mitochondrial morphology in primordial and preantral follicles.
  2. An aggregated mitochondrial distribution in preimplantation embryos disrupts nuclear morphology, function, and developmental potential.
  3. Age-associated increased stiffness of the ovarian microenvironment impairs follicle development and oocyte quality and rapidly alters follicle gene expression.
  4. Sirtuin 5-driven meiotic spindle assembly and actin-based migration in mouse oocyte meiosis.
  5. The role of declining ataxia-telangiectasia-mutated (ATM) function in oocyte aging.
  6. TENT5-mediated polyadenylation of mRNAs encoding secreted proteins is essential for gametogenesis in mice.
  7. p38 MAPK as a gatekeeper of reprogramming in mouse migratory primordial germ cells.
  8. Shape of the first mitotic spindles impacts multinucleation in human embryos.
  9. Single-cell RNA sequencing of human oocytes reveals a differential transcriptomic profile associated with agar-like zona pellucida.
  10. An Update on Physiopathological Roles of Akt in the ReprodAKTive Mammalian Ovary.
  1. PLoS One. 2024 ;19(6): e0305912
    The impact of offspring and maternal obesogenic diets on adult offspring oocyte mitochondrial morphology in primordial and preantral follicles.
    Inne Xhonneux, Waleed F A Marei, Ben Meulders, Jens Slootmans, Isabel Pintelon, Jo L M R Leroy.
      Diet-induced obesity reduces oocyte quality mainly by impacting oocyte mitochondrial functions. Moreover, maternal obesity is associated with mitochondrial dysfunction in oocytes of their adult offspring. However, these effects were reported only in fully grown oocytes, mainly in the form of abnormal mitochondrial ultrastructure. It is unknown if obesogenic (OB) diets or maternal obesity already impact the primordial and preantral follicles. Considering the long duration and dynamics of folliculogenesis, determining the stage at which oocytes are affected and the extent of the damage is crucial for optimal reproductive management of obese patients and their daughters. Potential interaction between maternal and offspring diet effects are also not described, yet pivotal in our contemporary society. Therefore, here we examined the impact of OB diets on oocyte mitochondrial ultrastructure in primordial and activated preantral follicles in offspring from diet-induced obese or lean mothers. We used an outbred Swiss mouse model to increase the pathophysiological relevance to humans. Female mice were fed control or OB diets for 7 weeks, then mated with control males. Their female offspring were fed control or OB diets after weaning for 7 weeks (2-by-2 factorial design). Adult offspring ovarian sections were examined using transmission electron microscopy. We characterised and classified unique features of oocyte mitochondrial ultrastructure in the preantral follicles. An increase in mitochondrial matrix density was the most predominant change during follicle activation in secondary follicles, a feature that is linked with a higher mitochondrial activity. Maternal obesity increased mitochondrial density already in the primordial follicles suggesting an earlier increase in bioenergetic capacity. Maternal obesity did not induce abberant ultrastructure (abnormalities and defects) in primordial or preantral follicles. In contrast, offspring OB diet increased mitochondrial abnormalities in the primordial follicles. Further investigation of the consequences of these changes on oocyte metabolic regulation and stress levels during folliculogenesis is needed.
    DOI:  https://doi.org/10.1371/journal.pone.0305912
  2. Proc Natl Acad Sci U S A. 2024 Jul 02. 121(27): e2317316121
    An aggregated mitochondrial distribution in preimplantation embryos disrupts nuclear morphology, function, and developmental potential.
    In-Won Lee, Abbas Pirpour Tazehkand, Zi-Yi Sha, Deepak Adhikari, John Carroll.
      A dispersed cytoplasmic distribution of mitochondria is a hallmark of normal cellular organization. Here, we have utilized the expression of exogenous Trak2 in mouse oocytes and embryos to disrupt the dispersed distribution of mitochondria by driving them into a large cytoplasmic aggregate. Our findings reveal that aggregated mitochondria have minimal impact on asymmetric meiotic cell divisions of the oocyte. In contrast, aggregated mitochondria during the first mitotic division result in daughter cells with unequal sizes and increased micronuclei. Further, in two-cell embryos, microtubule-mediated centering properties of the mitochondrial aggregate prevent nuclear centration, distort nuclear shape, and inhibit DNA synthesis and the onset of embryonic transcription. These findings demonstrate the motor protein-mediated distribution of mitochondria throughout the cytoplasm is highly regulated and is an essential feature of cytoplasmic organization to ensure optimal cell function.
    Keywords:  Meiosis; Mitosis; Nuclear morphology; TRAK2; mitochondrial aggregation
    DOI:  https://doi.org/10.1073/pnas.2317316121
  3. bioRxiv. 2024 Jun 10. pii: 2024.06.09.598134. [Epub ahead of print]
    Age-associated increased stiffness of the ovarian microenvironment impairs follicle development and oocyte quality and rapidly alters follicle gene expression.
    Sara Pietroforte, Makenzie Plough, Farners Amargant.
      In humans, aging triggers cellular and tissue deterioration, and the female reproductive system is the first to show signs of decline. Reproductive aging is associated with decreased ovarian reserve, decreased quality of the remaining oocytes, and decreased production of the ovarian hormones estrogen and progesterone. With aging, both mouse and human ovaries become pro-fibrotic and stiff. However, whether stiffness directly impairs ovarian function, folliculogenesis, and oocyte quality is unknown. To answer this question, we cultured mouse follicles in alginate gels that mimicked the stiffness of reproductively young and old ovaries. Follicles cultured in stiff hydrogels exhibited decreased survival and growth, decreased granulosa cell viability and estradiol synthesis, and decreased oocyte quality. We also observed a reduction in the number of granulosa cell-oocyte transzonal projections. RNA sequencing revealed early changes in the follicle transcriptome in response to stiffness. Follicles cultured in a stiff environment had lower expression of genes related to follicle development and greater expression of genes related to inflammation and extracellular matrix remodeling than follicles cultured in a soft environment. Altogether, our findings suggest that ovarian stiffness directly modulates folliculogenesis and contributes to the progressive decline in oocyte quantity and quality observed in women of advanced maternal age.
    DOI:  https://doi.org/10.1101/2024.06.09.598134
  4. Heliyon. 2024 Jun 15. 10(11): e32466
    Sirtuin 5-driven meiotic spindle assembly and actin-based migration in mouse oocyte meiosis.
    Cong Ma, Xueke Zhang, Yingying Zhang, Hongzhen Ruan, Xiaofeng Xu, Caiyun Wu, Zhiming Ding, Yunxia Cao.
      Sirtuin 5 (Sirt5), a member of the Sirtuin family, is involved in various intracellular biological processes. However, the function of Sirt5 in oocyte maturation has not been clearly elucidated. In this study, we observed that Sirt5 was persistently expressed during the meiotic division of mouse oocytes, with a notable decline in expression in aging oocytes. Sirt5 inhibition led to the failure of the first polar body extrusion and induced cell cycle arrest, indicative of unsuccessful oocyte maturation. Furthermore, Sirt5 inhibition was associated with the extrusion of abnormally large polar bodies, suggesting disrupted asymmetric oocyte division. Mechanistically, the inhibition of Sirt5 resulted in aberrant spindle assembly and disordered chromosome alignment in oocytes. Moreover, Sirt5 inhibition caused the spindle to be centrally located in the oocyte without migrating to the cortical region, consequently preventing the formation of the actin cap. Further investigation revealed that Sirt5 inhibition notably diminished the expression of phosphorylated cofilin and profilin1, while increasing cytoplasmic F-actin levels. These findings suggest that Sirt5 inhibition during oocyte maturation adversely affects spindle assembly and chromosome alignment and disrupts actin dynamics impairing spindle migration and contributing to the failure of symmetric oocyte division and maturation.
    Keywords:  F-actin; Meosis; Oocyte; Sirtuin 5; Spindle migration
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e32466
  5. Cell Death Discov. 2024 Jun 25. 10(1): 302
    The role of declining ataxia-telangiectasia-mutated (ATM) function in oocyte aging.
    Reiko Suzuki, Xiujuan Tan, Katarzyna J Szymanska, Nada Kubikova, Columba Avila Perez, Dagan Wells, Kutluk H Oktay.
      Despite the advances in the understanding of reproductive physiology, the mechanisms underlying ovarian aging are still not deciphered. Recent research found an association between impaired ATM-mediated DNA double-strand break (DSB) repair mechanisms and oocyte aging. However, direct evidence connecting ATM-mediated pathway function decline and impaired oocyte quality is lacking. The objective of this study was to determine the role of ATM-mediated DNA DSB repair in the maintenance of oocyte quality in a mouse oocyte knockdown model. Gene interference, in vitro culture, parthenogenesis coupled with genotoxicity assay approaches, as well as molecular cytogenetic analyses based upon next-generation sequencing, were used to test the hypothesis that intact ATM function is critical in the maintenance of oocyte quality. We found that ATM knockdown impaired oocyte quality, resulting in poor embryo development. ATM knockdown significantly lowered or blocked the progression of meiosis in vitro, as well as retarding and reducing embryo cleavage after parthenogenesis. After ATM knockdown, all embryos were of poor quality, and none reached the blastocyst stage. ATM knockdown was also associated with an increased aneuploidy rate compared to controls. Finally, ATM knockdown increased the sensitivity of the oocytes to a genotoxic active metabolite of cyclophosphamide, with increased formation of DNA DSBs, reduced survival, and earlier apoptotic death compared to controls. These findings suggest a key role for ATM in maintaining oocyte quality and resistance to genotoxic stress, and that the previously observed age-induced decline in oocyte ATM function may be a prime factor contributing to oocyte aging.
    DOI:  https://doi.org/10.1038/s41420-024-02041-z
  6. Nat Commun. 2024 Jun 22. 15(1): 5331
    TENT5-mediated polyadenylation of mRNAs encoding secreted proteins is essential for gametogenesis in mice.
    Michał Brouze, Agnieszka Czarnocka-Cieciura, Olga Gewartowska, Monika Kusio-Kobiałka, Kamil Jachacy, Marcin Szpila, Bartosz Tarkowski, Jakub Gruchota, Paweł Krawczyk, Seweryn Mroczek, Ewa Borsuk, Andrzej Dziembowski.
      Cytoplasmic polyadenylation plays a vital role in gametogenesis; however, the participating enzymes and substrates in mammals remain unclear. Using knockout and knock-in mouse models, we describe the essential role of four TENT5 poly(A) polymerases in mouse fertility and gametogenesis. TENT5B and TENT5C play crucial yet redundant roles in oogenesis, with the double knockout of both genes leading to oocyte degeneration. Additionally, TENT5B-GFP knock-in females display a gain-of-function infertility effect, with multiple chromosomal aberrations in ovulated oocytes. TENT5C and TENT5D both regulate different stages of spermatogenesis, as shown by the sterility in males following the knockout of either gene. Finally, Tent5a knockout substantially lowers fertility, although the underlying mechanism is not directly related to gametogenesis. Through direct RNA sequencing, we discovered that TENT5s polyadenylate mRNAs encoding endoplasmic reticulum-targeted proteins essential for gametogenesis. Sequence motif analysis and reporter mRNA assays reveal that the presence of an endoplasmic reticulum-leader sequence represents the primary determinant of TENT5-mediated regulation.
    DOI:  https://doi.org/10.1038/s41467-024-49479-4
  7. Front Cell Dev Biol. 2024 ;12 1410177
    p38 MAPK as a gatekeeper of reprogramming in mouse migratory primordial germ cells.
    Daiji Okamura, Aoi Kohara, Yuta Chigi, Tomoka Katayama, Jafar Sharif, Jun Wu, Yumi Ito-Matsuoka, Yasuhisa Matsui.
      Mammalian germ cells are derived from primordial germ cells (PGCs) and ensure species continuity through generations. Unlike irreversible committed mature germ cells, migratory PGCs exhibit a latent pluripotency characterized by the ability to derive embryonic germ cells (EGCs) and form teratoma. Here, we show that inhibition of p38 mitogen-activated protein kinase (MAPK) by chemical compounds in mouse migratory PGCs enables derivation of chemically induced Embryonic Germ-like Cells (cEGLCs) that do not require conventional growth factors like LIF and FGF2/Activin-A, and possess unique naïve pluripotent-like characteristics with epiblast features and chimera formation potential. Furthermore, cEGLCs are regulated by a unique PI3K-Akt signaling pathway, distinct from conventional naïve pluripotent stem cells described previously. Consistent with this notion, we show by performing ex vivo analysis that inhibition of p38 MAPK in organ culture supports the survival and proliferation of PGCs and also potentially reprograms PGCs to acquire indefinite proliferative capabilities, marking these cells as putative teratoma-producing cells. These findings highlight the utility of our ex vivo model in mimicking in vivo teratoma formation, thereby providing valuable insights into the cellular mechanisms underlying tumorigenesis. Taken together, our research underscores a key role of p38 MAPK in germ cell development, maintaining proper cell fate by preventing unscheduled pluripotency and teratoma formation with a balance between proliferation and differentiation.
    Keywords:  EGCs; gatekeeper; migratory primordial germ cells; p38 MAPK; pluripotency; reprogramming; teratoma
    DOI:  https://doi.org/10.3389/fcell.2024.1410177
  8. Nat Commun. 2024 Jun 25. 15(1): 5381
    Shape of the first mitotic spindles impacts multinucleation in human embryos.
    Yuki Ono, Hiromitsu Shirasawa, Kazumasa Takahashi, Mayumi Goto, Takahiro Ono, Taichi Sakaguchi, Motonari Okabe, Takeo Hirakawa, Takuya Iwasawa, Akiko Fujishima, Tae Sugawara, Kenichi Makino, Hiroshi Miura, Noritaka Fukunaga, Yoshimasa Asada, Yukiyo Kumazawa, Yukihiro Terada.
      During human embryonic development, early cleavage-stage embryos are more susceptible to errors. Studies have shown that many problems occur during the first mitosis, such as direct cleavage, chromosome segregation errors, and multinucleation. However, the mechanisms whereby these errors occur during the first mitosis in human embryos remain unknown. To clarify this aspect, in the present study, we image discarded living human two-pronuclear stage zygotes using fluorescent labeling and confocal microscopy without microinjection of DNA or mRNA and investigate the association between spindle shape and nuclear abnormality during the first mitosis. We observe that the first mitotic spindles vary, and low-aspect-ratio-shaped spindles tend to lead to the formation of multiple nuclei at the 2-cell stage. Moreover, we observe defocusing poles in many of the first mitotic spindles, which are strongly associated with multinucleation. Additionally, we show that differences in the positions of the centrosomes cause spindle abnormality in the first mitosis. Furthermore, many multinuclei are modified to form mononuclei after the second mitosis because the occurrence of pole defocusing is firmly reduced. Our study will contribute markedly to research on the occurrence of mitotic errors during the early cleavage of human embryos.
    DOI:  https://doi.org/10.1038/s41467-024-49815-8
  9. J Ovarian Res. 2024 Jun 26. 17(1): 132
    Single-cell RNA sequencing of human oocytes reveals a differential transcriptomic profile associated with agar-like zona pellucida.
    Xiangyang Zhang, Senlin Shi, Ying Wan, Wenyan Song, Haixia Jin, Yingpu Sun.
       BACKGROUND: Agar-like zona pellucida (ZP) is the most common type of abnormal ZP, and is one of the causes of low fertility or infertility. However, the molecular mechanism of agar-like ZP is unclear. Single-cell RNA-sequencing (scRNA-seq) analysis was used to assess the cellular and molecular landscape of oocytes with agar-like ZP.
    METHODS: Human metaphase I (MI) oocytes were collected from four patients with agar-like ZP and four healthy donors. Total RNA was isolated, cDNA was synthesized, and libraries were generated and subsequently sequenced on a HiSeq 2500 instrument. The scRNA-seq data were analyzed with R software.
    RESULTS: We identified 1320 genes that were differentially expressed between agar-like ZP oocytes and healthy donor oocytes. Gene Ontology term enrichment results showed that the genes downregulated in agar-like ZP oocytes were significantly related to extracellular matrix organization, while the genes upregulated in agar-like ZP oocytes were significantly related to the regulation of response to DNA damage stimulus. The Kyoto Encyclopedia of Genes and Genomes enrichment results showed that genes were enriched in the ECM-receptor interaction pathway and focal adhesion pathway. Other signaling pathways important in oocyte development were also enriched, such as PI3K-Akt. Differential expression analysis identified UBC, TLR4, RELA, ANXA5, CAV1, KPNA2, CCNA2, ACTA2, FYN and ITGB3 as genetic markers of oocytes with agar-like ZP.
    CONCLUSIONS: Our findings suggest that agar-like ZP oocytes exhibit significant downregulation of genes involved in the ECM-receptor interaction signaling pathway and focal adhesion pathway, which could lead to aberrant ZP formation, while the upregulated genes were significantly related to regulation of the response to DNA damage stimulus. Agar-like ZP formation may interfere with the normal exchange of signals between oocytes and perivitelline granulosa cells, thereby preventing cumulus cells from participating in oocyte DNA damage repair and causing MI arrest.
    Keywords:  Agar-like zona pellucida; Human oocyte; Transcriptomic analysis; scRNA-seq
    DOI:  https://doi.org/10.1186/s13048-024-01463-8
  10. Life (Basel). 2024 Jun 02. pii: 722. [Epub ahead of print]14(6):
    An Update on Physiopathological Roles of Akt in the ReprodAKTive Mammalian Ovary.
    Carlo Giaccari, Sevastiani Antonouli, George Anifandis, Sandra Cecconi, Valentina Di Nisio.
      The phosphoinositide 3-kinase (PI3K)/Akt pathway is a key signaling cascade responsible for the regulation of cell survival, proliferation, and metabolism in the ovarian microenvironment. The optimal finetuning of this pathway is essential for physiological processes concerning oogenesis, folliculogenesis, oocyte maturation, and embryo development. The dysregulation of PI3K/Akt can impair molecular and structural mechanisms that will lead to follicle atresia, or the inability of embryos to reach later stages of development. Due to its pivotal role in the control of cell proliferation, apoptosis, and survival mechanisms, the dysregulation of this molecular pathway can trigger the onset of pathological conditions. Among these, we will focus on diseases that can harm female fertility, such as polycystic ovary syndrome and premature ovarian failure, or women's general health, such as ovarian cancer. In this review, we report the functions of the PI3K/Akt pathway in both its physiological and pathological roles, and we address the existing application of inhibitors and activators for the balancing of the molecular cascade in ovarian pathological environments.
    Keywords:  PCOS; PI3K/Akt pathway; POF; folliculogenesis; ovarian cancer; ovary
    DOI:  https://doi.org/10.3390/life14060722
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