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Cell Feb 2024Oocytes are among the longest-lived cells in the body and need to preserve their cytoplasm to support proper embryonic development. Protein aggregation is a major threat...
Oocytes are among the longest-lived cells in the body and need to preserve their cytoplasm to support proper embryonic development. Protein aggregation is a major threat for intracellular homeostasis in long-lived cells. How oocytes cope with protein aggregation during their extended life is unknown. Here, we find that mouse oocytes accumulate protein aggregates in specialized compartments that we named endolysosomal vesicular assemblies (ELVAs). Combining live-cell imaging, electron microscopy, and proteomics, we found that ELVAs are non-membrane-bound compartments composed of endolysosomes, autophagosomes, and proteasomes held together by a protein matrix formed by RUFY1. Functional assays revealed that in immature oocytes, ELVAs sequester aggregated proteins, including TDP-43, and degrade them upon oocyte maturation. Inhibiting degradative activity in ELVAs leads to the accumulation of protein aggregates in the embryo and is detrimental for embryo survival. Thus, ELVAs represent a strategy to safeguard protein homeostasis in long-lived cells.
Topics: Animals; Female; Mice; Autophagosomes; Cytoplasmic Vesicles; Lysosomes; Oocytes; Proteasome Endopeptidase Complex; Protein Aggregates; Proteolysis
PubMed: 38382525
DOI: 10.1016/j.cell.2024.01.031 -
Cell Apr 2024Nucleoli are multicomponent condensates defined by coexisting sub-phases. We identified distinct intrinsically disordered regions (IDRs), including acidic (D/E) tracts...
Nucleoli are multicomponent condensates defined by coexisting sub-phases. We identified distinct intrinsically disordered regions (IDRs), including acidic (D/E) tracts and K-blocks interspersed by E-rich regions, as defining features of nucleolar proteins. We show that the localization preferences of nucleolar proteins are determined by their IDRs and the types of RNA or DNA binding domains they encompass. In vitro reconstitutions and studies in cells showed how condensation, which combines binding and complex coacervation of nucleolar components, contributes to nucleolar organization. D/E tracts of nucleolar proteins contribute to lowering the pH of co-condensates formed with nucleolar RNAs in vitro. In cells, this sets up a pH gradient between nucleoli and the nucleoplasm. By contrast, juxta-nucleolar bodies, which have different macromolecular compositions, featuring protein IDRs with very different charge profiles, have pH values that are equivalent to or higher than the nucleoplasm. Our findings show that distinct compositional specificities generate distinct physicochemical properties for condensates.
Topics: Cell Nucleolus; Cell Nucleus; Nuclear Proteins; Proton-Motive Force; RNA; Phase Separation; Intrinsically Disordered Proteins; Animals; Xenopus laevis; Oocytes
PubMed: 38503281
DOI: 10.1016/j.cell.2024.02.029 -
Current Biology : CB Jun 2024Rapid cleavage divisions and the transition from maternal to zygotic control of gene expression are the hallmarks of early embryonic development in most species. Early... (Review)
Review
Rapid cleavage divisions and the transition from maternal to zygotic control of gene expression are the hallmarks of early embryonic development in most species. Early development in insects, fish and amphibians is characterized by several short cell cycles with no gap phases, necessary for the rapid production of cells prior to patterning and morphogenesis. Maternal mRNAs and proteins loaded into the egg during oogenesis are essential to drive these rapid early divisions. Once the function of these maternal inputs is complete, the maternal-to-zygotic transition (MZT) marks the handover of developmental control to the gene products synthesized from the zygotic genome. The MZT requires three major events: the removal of a subset of maternal mRNAs, the initiation of zygotic transcription, and the remodeling of the cell cycle. In each species, the MZT occurs at a highly reproducible time during development due to a series of feedback mechanisms that tightly couple these three processes. Dissecting these feedback mechanisms and their spatiotemporal control will be essential to understanding the control of the MZT. In this primer, we outline the mechanisms that govern the major events of the MZT across species and highlight the role of feedback mechanisms that ensure the MZT is precisely timed and orchestrated.
Topics: Zygote; Animals; Gene Expression Regulation, Developmental; Embryonic Development; Female; RNA, Messenger, Stored
PubMed: 38834020
DOI: 10.1016/j.cub.2024.04.044 -
Aging Aug 2023
Topics: Oocytes; Epigenesis, Genetic
PubMed: 37552096
DOI: 10.18632/aging.204976 -
Journal of Cell Science Aug 2023Cellular quiescence is a dormant, non-dividing cell state characterized by significant shifts in physiology and metabolism. Quiescence plays essential roles in a wide... (Review)
Review
Cellular quiescence is a dormant, non-dividing cell state characterized by significant shifts in physiology and metabolism. Quiescence plays essential roles in a wide variety of biological processes, ranging from microbial sporulation to human reproduction and wound repair. Moreover, when the regulation of quiescence is disrupted, it can drive cancer growth and compromise tissue regeneration after injury. In this Review, we examine the dynamic changes in metabolism that drive and support dormant and transiently quiescent cells, including spores, oocytes and adult stem cells. We begin by defining quiescent cells and discussing their roles in key biological processes. We then examine metabolic factors that influence cellular quiescence in both healthy and disease contexts, and how these could be leveraged in the treatment of cancer.
Topics: Adult; Humans; Cell Division; Oocytes; Wound Healing
PubMed: 37589342
DOI: 10.1242/jcs.260787 -
Frontiers in Endocrinology 2024
Topics: Oocytes; Aging
PubMed: 38298380
DOI: 10.3389/fendo.2024.1361115 -
Nucleic Acids Research Dec 2023Translation is critical for development as transcription in the oocyte and early embryo is silenced. To illustrate the translational changes during meiosis and...
Translation is critical for development as transcription in the oocyte and early embryo is silenced. To illustrate the translational changes during meiosis and consecutive two mitoses of the oocyte and early embryo, we performed a genome-wide translatome analysis. Acquired data showed significant and uniform activation of key translational initiation and elongation axes specific to M-phases. Although global protein synthesis decreases in M-phases, translation initiation and elongation activity increases in a uniformly fluctuating manner, leading to qualitative changes in translation regulation via the mTOR1/4F/eEF2 axis. Overall, we have uncovered a highly dynamic and oscillatory pattern of translational reprogramming that contributes to the translational regulation of specific mRNAs with different modes of polysomal occupancy/translation that are important for oocyte and embryo developmental competence. Our results provide new insights into the regulation of gene expression during oocyte meiosis as well as the first two embryonic mitoses and show how temporal translation can be optimized. This study is the first step towards a comprehensive analysis of the molecular mechanisms that not only control translation during early development, but also regulate translation-related networks employed in the oocyte-to-embryo transition and embryonic genome activation.
Topics: Embryonic Development; Gene Expression Regulation, Developmental; Meiosis; Oocytes; Protein Biosynthesis; RNA, Messenger; Animals; Mice
PubMed: 37950888
DOI: 10.1093/nar/gkad996 -
Development (Cambridge, England) Sep 2023Male germ cells undergo a complex sequence of developmental events throughout fetal and postnatal life that culminate in the formation of haploid gametes: the...
Male germ cells undergo a complex sequence of developmental events throughout fetal and postnatal life that culminate in the formation of haploid gametes: the spermatozoa. Errors in these processes result in infertility and congenital abnormalities in offspring. Male germ cell development starts when pluripotent cells undergo specification to sexually uncommitted primordial germ cells, which act as precursors of both oocytes and spermatozoa. Male-specific development subsequently occurs in the fetal testes, resulting in the formation of spermatogonial stem cells: the foundational stem cells responsible for lifelong generation of spermatozoa. Although deciphering such developmental processes is challenging in humans, recent studies using various models and single-cell sequencing approaches have shed new insight into human male germ cell development. Here, we provide an overview of cellular, signaling and epigenetic cascades of events accompanying male gametogenesis, highlighting conserved features and the differences between humans and other model organisms.
Topics: Male; Humans; Germ Cells; Spermatozoa; Oocytes; Adult Germline Stem Cells; Cell Differentiation
PubMed: 37650565
DOI: 10.1242/dev.202046 -
Nature Communications Nov 2023Embryo development depends upon maternally derived materials. Mammalian oocytes undergo extreme asymmetric cytokinesis events, producing one large egg and two small...
Embryo development depends upon maternally derived materials. Mammalian oocytes undergo extreme asymmetric cytokinesis events, producing one large egg and two small polar bodies. During cytokinesis in somatic cells, the midbody and subsequent assembly of the midbody remnant, a signaling organelle containing RNAs, transcription factors and translation machinery, is thought to influence cellular function or fate. The role of the midbody and midbody remnant in gametes, in particular, oocytes, remains unclear. Here, we examined the formation and function of meiotic midbodies (mMB) and mMB remnants using mouse oocytes and demonstrate that mMBs have a specialized cap structure that is orientated toward polar bodies. We show that that mMBs are translationally active, and that mMB caps are required to retain nascent proteins in eggs. We propose that this specialized mMB cap maintains genetic factors in eggs allowing for full developmental competency.
Topics: Animals; Mice; Meiosis; Oocytes; Cytokinesis; Polar Bodies; Embryonic Development; Mammals
PubMed: 37973997
DOI: 10.1038/s41467-023-43288-x -
Yi Chuan = Hereditas Dec 2023Normal oogenesis is crucial to successful reproduction. During the human female fetal stage, primordial germ cells transform from mitosis to meiosis. After synapsis and... (Review)
Review
Normal oogenesis is crucial to successful reproduction. During the human female fetal stage, primordial germ cells transform from mitosis to meiosis. After synapsis and recombination of homologous chromosomes, meiosis is arrested at the diplotene stage of prophase in meiosis I. The maintenance of oocyte meiotic arrest in the follicle is primarily attributed to high cytoplasmic concentrations of cyclic adenosine monophosphate. During the menstrual cycle, follicle-stimulating hormone and luteinizing hormone lead to the resumption of meiosis that occurs in certain oocytes and complete the ovulation process. Anything that disturbs oocyte meiosis may result in failure of oogenesis and seriously affect both the fertilization and embryonic development. The rapid development of the assisted reproduction technology, high-throughput sequencing technology, and molecular biology technology provide new ideas and means for human to understand molecular mechanism of meiosis and diagnosis and treatment of oocyte maturation defects. In this review, we mainly summarize the recent physiological and pathological mechanisms of oogenesis, involving homologous recombination, meiotic arrest and resumption, maternal mRNA degradation, post-translational regulation, zona pellucida assembly, and so on. We wish to take this opportunity to raise the awareness of researchers in related fields on oocyte meiosis, providing a theoretical basis for further research and disease treatments.
Topics: Meiosis; Oocytes; Humans; Female; Oogenesis; Animals
PubMed: 38764273
DOI: 10.16288/j.yczz.23-170