bims-cebooc Biomed News
on Cell biology of oocytes
Issue of 2024–12–15
seven papers selected by
Gabriele Zaffagnini, Universität zu Köln
  1. Hallmarks of female reproductive aging in physiologic aging mice.
  2. Emerging therapeutic strategies to mitigate female and male reproductive aging.
  3. Novel BRCA1-PLK1-CIP2A axis orchestrates homologous recombination-mediated DNA repair to maintain chromosome integrity during oocyte meiosis.
  4. The role of ER exit sites in maintaining P-body organization and integrity during Drosophila melanogaster oogenesis.
  5. Female-germline specific protein Sakura interacts with Otu and is crucial for germline stem cell renewal and differentiation and oogenesis.
  6. Caspar specifies primordial germ cell count and identity in Drosophila melanogaster.
  7. Piwi regulates the usage of alternative transcription start sites in the Drosophila ovary.
  1. Nat Aging. 2024 Dec;4(12): 1711-1730
    Hallmarks of female reproductive aging in physiologic aging mice.
    Julia L Balough, Shweta S Dipali, Karen Velez, T Rajendra Kumar, Francesca E Duncan.
      The female reproductive axis is one of the first organ systems to age, which has consequences for fertility and overall health. Here, we provide a comprehensive overview of the biological process of female reproductive aging across reproductive organs, tissues and cells based on research with widely used physiologic aging mouse models, and describe the mechanisms that underpin these phenotypes. Overall, aging is associated with dysregulation of the hypothalamic-pituitary-ovarian axis, perturbations of the ovarian stroma, reduced egg quantity and quality, and altered uterine morphology and function that contributes to reduced capacity for fertilization and impaired embryo development. Ultimately, these age-related phenotypes contribute to altered pregnancy outcomes and adverse consequences in offspring. Conserved mechanisms of aging, as well as those unique to the reproductive system, underlie these phenotypes. The knowledge of such mechanisms will lead to development of therapeutics to extend female reproductive longevity and support endocrine function and overall health.
    DOI:  https://doi.org/10.1038/s43587-024-00769-y
  2. Nat Aging. 2024 Dec;4(12): 1682-1696
    Emerging therapeutic strategies to mitigate female and male reproductive aging.
    Yasmyn E Winstanley, Jennifer S Stables, Macarena B Gonzalez, Takashi Umehara, Robert J Norman, Rebecca L Robker.
      People today are choosing to have children later in life, often in their thirties and forties, when their fertility is in decline. We sought to identify and compile effective methods for improving either male or female fertility in this context of advanced reproductive age. We found few clinical studies with strong evidence for therapeutics that mitigate reproductive aging or extend fertility; however, this Perspective summarizes the range of emerging experimental strategies under development. Preclinical studies, in mouse models of aging, have identified pharmaceutical candidates that improve egg and sperm quality. Further, a diverse array of medically assisted reproduction methodologies, including those that stimulate rare ovarian follicles and rejuvenate egg quality using mitochondria, may have future utility for older patients. Finally, we highlight the many knowledge gaps and possible future directions in the field of therapeutics to extend the age of healthy human reproduction.
    DOI:  https://doi.org/10.1038/s43587-024-00771-4
  3. Nucleic Acids Res. 2024 Dec 09. pii: gkae1207. [Epub ahead of print]
    Novel BRCA1-PLK1-CIP2A axis orchestrates homologous recombination-mediated DNA repair to maintain chromosome integrity during oocyte meiosis.
    Crystal Lee, Jeong Su Oh.
      Double-strand breaks (DSBs) are a formidable threat to genome integrity, potentially leading to cancer and various genetic diseases. The prolonged lifespan of mammalian oocytes increases their susceptibility to DNA damage over time. While somatic cells suppress DSB repair during mitosis, oocytes exhibit a remarkable capacity to repair DSBs during meiotic maturation. However, the precise mechanisms underlying DSB repair in oocytes remain poorly understood. Here, we describe the pivotal role of the BRCA1-PLK1-CIP2A axis in safeguarding genomic integrity during meiotic maturation in oocytes. We found that inhibition of homologous recombination (HR) severely impaired chromosome integrity by generating chromosome fragments during meiotic maturation. Notably, HR inhibition impaired the recruitment of CIP2A to damaged chromosomes, and the depletion of CIP2A led to chromosome fragmentation following DSB induction. Moreover, BRCA1 depletion impaired chromosomal recruitment of CIP2A, but not vice versa. Importantly, the impaired chromosomal recruitment of CIP2A could be rescued by PLK1 inhibition. Consequently, our findings not only underscore the importance of the chromosomal recruitment of CIP2A in preventing chromosome fragmentation, but also demonstrate the regulatory role of the BRCA1-PLK1-CIP2A axis in this process during oocyte meiotic maturation.
    DOI:  https://doi.org/10.1093/nar/gkae1207
  4. EMBO Rep. 2024 Dec 09.
    The role of ER exit sites in maintaining P-body organization and integrity during Drosophila melanogaster oogenesis.
    Samantha N Milano, Livia V Bayer, Julie J Ko, Caroline E Casella, Diana P Bratu.
      Processing bodies (P-bodies) are cytoplasmic membrane-less organelles which host multiple mRNA processing events. While the fundamental principles of P-body organization are beginning to be elucidated in vitro, a nuanced understanding of how their assembly is regulated in vivo remains elusive. Here, we investigate the potential link between ER exit sites and P-bodies in Drosophila melanogaster egg chambers. Employing a combination of live and super-resolution imaging, we find that P-bodies associated with ER exit sites are larger and less mobile than cytoplasmic P-bodies, indicating that they constitute a distinct class of P-bodies. Moreover, we demonstrate that altering the composition of ER exit sites has differential effects on core P-body proteins (Me31B, Cup, and Trailer Hitch), suggesting a potential role for ER exit sites in P-body organization. Furthermore, we show that in the absence of ER exit sites, P-body integrity is compromised and the stability and translational repression efficiency of the maternal mRNA, oskar, are reduced. Together, our data highlights the crucial role of ER exit sites in governing P-body organization.
    Keywords:  Biological Condensates; ER Exit Sites; Oogenesis; P-bodies; Post-transcriptional Regulation
    DOI:  https://doi.org/10.1038/s44319-024-00344-x
  5. bioRxiv. 2024 Nov 28. pii: 2024.10.04.616675. [Epub ahead of print]
    Female-germline specific protein Sakura interacts with Otu and is crucial for germline stem cell renewal and differentiation and oogenesis.
    Azali Azlan, Li Zhu, Ryuya Fukunaga.
      During oogenesis, self-renewal and differentiation of germline stem cells (GSCs) must be tightly regulated. The Drosophila female germline serves as an excellent model for studying these regulatory mechanisms. Here, we report that a previously uncharacterized gene CG14545 , which we named sakura , is essential for oogenesis and female fertility in Drosophila . Sakura is predominantly expressed in the ovaries, particularly in the germline cells, including GSCs. sakura null mutant female flies display rudimentary ovaries with germline-less and tumorous phenotypes, fail to produce eggs, and are completely sterile. The germline-specific depletion of sakura impairs Dpp/BMP signaling, leading to aberrant bag-of-marbles ( bam ) expression, resulting in faulty differentiation and loss of GSCs. Additionally, sakura is necessary for normal piwi-interacting RNAs (piRNAs) levels and for proper localization of Ool8 RNA-binding protein (Orb) in developing oocytes. We identified Ovarian Tumor (Otu) as protein binding partner of Sakura, and we found that loss of otu phenocopies loss of sakura in ovaries. Thus, we identified Sakura as a crucial factor for GSC renewal and differentiation and oogenesis, and propose that Sakura and Otu function together in these processes.
    DOI:  https://doi.org/10.1101/2024.10.04.616675
  6. Elife. 2024 Dec 13. pii: RP98584. [Epub ahead of print]13
    Caspar specifies primordial germ cell count and identity in Drosophila melanogaster.
    Subhradip Das, Sushmitha Hegde, Neel Wagh, Jyothish Sudhakaran, Adheena Elsa Roy, Girish Deshpande, Girish S Ratnaparkhi.
      Repurposing of pleiotropic factors during execution of diverse cellular processes has emerged as a regulatory paradigm. Embryonic development in metazoans is controlled by maternal factors deposited in the egg during oogenesis. Here, we explore maternal role(s) of Caspar (Casp), the Drosophila orthologue of human Fas-associated factor-1 (FAF1) originally implicated in host-defense as a negative regulator of NF-κB signaling. Maternal loss of either Casp or it's protein partner, transitional endoplasmic reticulum 94 (TER94) leads to partial embryonic lethality correlated with aberrant centrosome behavior, cytoskeletal abnormalities, and defective gastrulation. Although ubiquitously distributed, both proteins are enriched in the primordial germ cells (PGCs), and in keeping with the centrosome problems, mutant embryos display a significant reduction in the PGC count. Moreover, the total number of pole buds is directly proportional to the level of Casp. Consistently, it's 'loss' and 'gain' results in respective reduction and increase in the Oskar protein levels, the master determinant of PGC fate. To elucidate this regulatory loop, we analyzed several known components of mid-blastula transition and identify the translational repressor Smaug, a zygotic regulator of germ cell specification, as a potential critical target. We present a detailed structure-function analysis of Casp aimed at understanding its novel involvement during PGC development.
    Keywords:  D. melanogaster; MZT; centrosome; degradation; developmental biology; genetics; genomics; maternal-to-zygotic transition; pindle; pole cells
    DOI:  https://doi.org/10.7554/eLife.98584
  7. Nucleic Acids Res. 2024 Dec 09. pii: gkae1160. [Epub ahead of print]
    Piwi regulates the usage of alternative transcription start sites in the Drosophila ovary.
    Jiaying Chen, Na Liu, Hongying Qi, Nils Neuenkirchen, Yuedong Huang, Haifan Lin.
      Alternative transcription initiation, which refers to the transcription of a gene from different transcription start sites (TSSs), is prevalent across metazoans and has important biological functions. Although transcriptional regulation has been extensively studied, the mechanism that selects one TSS over others within a gene remains elusive. Using the Cap Analysis of Gene Expression sequencing (CAGE-seq) method, we discovered that Piwi, an RNA-binding protein, regulates TSS usage in at least 87 genes. In piwi-deficient Drosophila ovaries, these genes displayed significantly altered TSS usage (ATU). The regulation of TSS usage occurred in both germline and somatic cells in ovaries, as well as in cultured ovarian somatic cells (OSCs). Correspondingly, RNA Polymerase II (Pol II) initiation and elongation at the TSSs of ATU genes were affected in germline-piwi-knockdown ovaries and piwi-knockdown OSCs. Furthermore, we identified a Facilitates Chromatin Transcription (FACT) complex component, Ssrp, that is essential for mRNA elongation, as a novel interactor of Piwi in the nucleus. Temporally controlled knockdown of ssrp affected TSS usage in ATU genes, whereas overexpression of ssrp partially rescued the TSS usage of ATU genes in piwi mutant ovaries. Thus, Piwi may interact with Ssrp to regulate TSS usage in Drosophila ovaries by affecting Pol II initiation and elongation.
    DOI:  https://doi.org/10.1093/nar/gkae1160
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