bims-cebooc 2024-10-27 papers

bims-cebooc

Biomed News

on Cell biology of oocytes

Issue of 2024–10–27
six papers selected by
Gabriele Zaffagnini, Centre for Genomic Regulation

Changes in DNA repair compartments and cohesin loss promote DNA damage accumulation in aged oocytes.
Mutation of the SUMOylation site of Aurora-B disrupts spindle formation and chromosome alignment in oocytes.
Transcriptomic signatures of WNT-driven pathways and granulosa cell-oocyte interactions during primordial follicle activation.
How the Oocyte Nucleolus Is Turned into a Karyosphere: The Role of Heterochromatin and Structural Proteins.
Follicle-intrinsic and spatially distinct molecular programs drive follicle rupture and luteinization during ex vivo mammalian ovulation.
Transgenerational transmission of post-zygotic mutations suggests symmetric contribution of first two blastomeres to human germline.

Curr Biol. 2024 Oct 17. pii: S0960-9822(24)01281-8. [Epub ahead of print]

Changes in DNA repair compartments and cohesin loss promote DNA damage accumulation in aged oocytes.

Ninadini Sharma, Giovanni Coticchio, Andrea Borini, Kikuë Tachibana, Kim A Nasmyth, Melina Schuh.

  Oocyte loss, a natural process that accelerates as women approach their mid-30s, poses a significant challenge to female reproduction. Recent studies have identified DNA damage as a primary contributor to oocyte loss, but the mechanisms underlying DNA damage accumulation remain unclear. Here, we show that aged oocytes have a lower DNA repair capacity and reduced mobility of DNA damage sites compared to young oocytes. Incomplete DNA repair in aged oocytes results in defective chromosome integrity and partitioning, thereby compromising oocyte quality. We found that DNA repair proteins are arranged in spatially distinct DNA repair compartments that form during the late stages of oocyte growth, accompanied by changes in the activity of DNA repair pathways. We demonstrate alterations in these compartments with age, including substantial changes in the levels of key DNA repair proteins and a shift toward error-prone DNA repair pathways. In addition, we show that reduced cohesin levels make aged oocytes more vulnerable to persistent DNA damage and cause changes in DNA repair compartments. Our study links DNA damage accumulation in aged oocytes, a leading cause of oocyte loss, to cohesin deterioration and changes in the organization, abundance, and response of DNA repair machinery.

Keywords:  DNA damage; DNA repair; aging; chromosome segregation; cohesin; fertility; meiosis; oocyte

DOI:  https://doi.org/10.1016/j.cub.2024.09.040
Cell Death Discov. 2024 Oct 22. 10(1): 447

Mutation of the SUMOylation site of Aurora-B disrupts spindle formation and chromosome alignment in oocytes.

Shan-Shan Chen, Li Li, Bo Yao, Jia-Lun Guo, Ping-Shuang Lu, Hao-Lin Zhang, Kun-Huan Zhang, Yuan-Jing Zou, Nan-Jian Luo, Shao-Chen Sun, Lin-Lin Hu, Yan-Ping Ren.

Aurora-B is a kinase that regulates spindle assembly and kinetochore-microtubule (KT-MT) attachment during mitosis and meiosis. SUMOylation is involved in the oocyte meiosis regulation through promoting spindle assembly and chromosome segregation, but its substrates to support this function is still unknown. It is reported that Aurora-B is SUMOylated in somatic cells, and SUMOylated Aurora-B contributes the process of mitosis. However, whether Aurora-B is SUMOylated in oocytes and how SUMOylation of Aurora-B impacts its function in oocyte meiosis remain poorly understood. In this study, we report that Aurora-B is modified by SUMOylation in mouse oocytes. The results show that Aurora-B colocalized and interacted with SUMO-2/3 in mouse oocytes, confirming that Aurora-B is modified by SUMO-2/3 in this system. Compared with that in young mice, the protein expression of SUMO-2/3 decreased in the oocytes of aged mice, indicating that SUMOylation might be related to mouse aging. Overexpression of Aurora-B SUMOylation site mutants, Aurora-BK207R and Aurora-BK292R, inhibited Aurora-B recruitment and first polar body extrusion, disrupting localization of gamma tubulin, spindle formation and chromosome alignment in oocytes. The results show that it was related to decreased recruitment of p-HDAC6 which induces the high stability of whole spindle microtubules including the microtubules of both correct and wrong KT-MT attachments though increased acetylation of microtubules. Therefore, our results corroborate the notion that Aurora-B activity is regulated by SUMO-2/3 in oocytes, and that SUMOylated Aurora B plays an important role in spindle formation and chromosome alignment.

DOI: https://doi.org/10.1038/s41420-024-02217-7
PLoS One. 2024 ;19(10): e0311978

Transcriptomic signatures of WNT-driven pathways and granulosa cell-oocyte interactions during primordial follicle activation.

Hinako M Takase, Tappei Mishina, Tetsutaro Hayashi, Mika Yoshimura, Mariko Kuse, Itoshi Nikaido, Tomoya S Kitajima.

Primordial follicle activation (PFA) is a pivotal event in female reproductive biology, coordinating the transition from quiescent to growing follicles. This study employed comprehensive single-cell RNA sequencing to gain insights into the detailed regulatory mechanisms governing the synchronized dormancy and activation between granulosa cells (GCs) and oocytes with the progression of the PFA process. Wntless (Wls) conditional knockout (cKO) mice served as a unique model, suppressing the transition from pre-GCs to GCs, and disrupting somatic cell-derived WNT signaling in the ovary. Our data revealed immediate transcriptomic changes in GCs post-PFA in Wls cKO mice, leading to a divergent trajectory, while oocytes exhibited modest transcriptomic alterations. Subpopulation analysis identified the molecular pathways affected by WNT signaling on GC maturation, along with specific gene signatures linked to dormant and activated oocytes. Despite minimal evidence of continuous up-regulation of dormancy-related genes in oocytes, the loss of WNT signaling in (pre-)GCs impacted gene expression in oocytes even before PFA, subsequently influencing them globally. The infertility observed in Wls cKO mice was attributed to compromised GC-oocyte molecular crosstalk and the microenvironment for oocytes. Our study highlights the pivotal role of the WNT-signaling pathway and its molecular signature, emphasizing the importance of intercellular crosstalk between (pre-)GCs and oocytes in orchestrating folliculogenesis.

DOI: https://doi.org/10.1371/journal.pone.0311978
J Dev Biol. 2024 Oct 18. pii: 28. [Epub ahead of print]12(4):

How the Oocyte Nucleolus Is Turned into a Karyosphere: The Role of Heterochromatin and Structural Proteins.

Venera Nikolova, Maya Markova, Ralitsa Zhivkova, Irina Chakarova, Valentina Hadzhinesheva, Stefka Delimitreva.

  Oocyte meiotic maturation includes large-scale chromatin remodeling as well as cytoskeleton and nuclear envelope rearrangements. This review addresses the dynamics of key cytoskeletal proteins (tubulin, actin, vimentin, and cytokeratins) and nuclear envelope proteins (lamin A/C, lamin B, and the nucleoporin Nup160) in parallel with chromatin reorganization in maturing mouse oocytes. A major feature of this reorganization is the concentration of heterochromatin into a spherical perinucleolar rim called surrounded nucleolus or karyosphere. In early germinal vesicle (GV) oocytes with non-surrounded nucleolus (without karyosphere), lamins and Nup160 are at the nuclear envelope while cytoplasmic cytoskeletal proteins are outside the nucleus. At the beginning of karyosphere formation, lamins and Nup160 follow the heterochromatin relocation assembling a new spherical structure in the GV. In late GV oocytes with surrounded nucleolus (fully formed karyosphere), the nuclear envelope gradually loses its integrity and cytoplasmic cytoskeletal proteins enter the nucleus. At germinal vesicle breakdown, lamin B occupies the karyosphere interior while all the other proteins stay at the karyosphere border or connect to chromatin. In metaphase oocytes, lamin A/C surrounds the spindle, Nup160 localizes to its poles, actin and lamin B are attached to the spindle fibers, and cytoplasmic intermediate filaments associate with both the spindle fibers and the metaphase chromosomes.

Keywords:  cytoskeleton; germinal vesicle; karyosphere; meiosis; meiotic spindle; nuclear envelope; nuclear lamina; oocytes

DOI:  https://doi.org/10.3390/jdb12040028
Commun Biol. 2024 Oct 23. 7(1): 1374

Follicle-intrinsic and spatially distinct molecular programs drive follicle rupture and luteinization during ex vivo mammalian ovulation.

Emily J Zaniker, Jiyang Zhang, Daniela Russo, Ruixu Huang, Kristine Suritis, Riley S Drake, Esther Barlow-Smith, Alex K Shalek, Teresa K Woodruff, Shuo Xiao, Brittany A Goods, Francesca E Duncan.

During ovulation, the apical wall of the preovulatory follicle breaks down to facilitate gamete release. In parallel, the residual follicle wall differentiates into a progesterone-producing corpus luteum. Disruption of ovulation, whether through contraceptive intervention or infertility, has implications for women's health. In this study, we harness the power of an ex vivo ovulation model and machine-learning guided microdissection to identify differences between the ruptured and unruptured sides of the follicle wall. We demonstrate that the unruptured side exhibits clear markers of luteinization after ovulation while the ruptured side exhibits cell death signals. RNA-sequencing of individual follicle sides reveals 2099 differentially expressed genes (DEGs) between follicle sides without ovulation induction, and 1673 DEGs 12 h after induction of ovulation. Our model validates molecular patterns consistent with known ovulation biology even though this process occurs in the absence of the ovarian stroma, vasculature, and immune cells. We further identify previously unappreciated pathways including amino acid transport and Jag-Notch signaling on the ruptured side and glycolysis, metal ion processing, and IL-11 signaling on the unruptured side of the follicle. This study yields key insights into follicle-inherent, spatially-defined pathways that underlie follicle rupture, which may further understanding of ovulation physiology and advance women's health.

DOI: https://doi.org/10.1038/s42003-024-07074-9
Nat Commun. 2024 Oct 23. 15(1): 9117

Transgenerational transmission of post-zygotic mutations suggests symmetric contribution of first two blastomeres to human germline.

Yeongjun Jang, Livia Tomasini, Taejeong Bae, Anna Szekely, Flora M Vaccarino, Alexej Abyzov.

Little is known about the origin of germ cells in humans. We previously leveraged post-zygotic mutations to reconstruct zygote-rooted cell lineage ancestry trees in a phenotypically normal woman, termed NC0. Here, by sequencing the genome of her children and their father, we analyze the transmission of early pre-gastrulation lineages and corresponding mutations across human generations. We find that the germline in NC0 is polyclonal and is founded by at least two cells likely descending from the two blastomeres arising from the first zygotic cleavage. Analyzes of public data from several multi-children families and from 1934 familial quads confirm this finding in larger cohorts, revealing that known imbalances of up to 90:10 in early lineages allocation in somatic tissues are not reflected in mutation transmission to offspring, establishing a fundamental difference in lineage allocation between the soma and the germline. Analyzes of all the data consistently suggest that the germline has a balanced 50:50 lineage allocation from the first two blastomeres.

DOI: https://doi.org/10.1038/s41467-024-53485-x