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Molecular Reproduction and Development Sep 2022During oogenesis, oocytes arrest at meiotic prophase I to acquire competencies for resuming meiosis, fertilization, and early embryonic development. Following this... (Review)
Review
During oogenesis, oocytes arrest at meiotic prophase I to acquire competencies for resuming meiosis, fertilization, and early embryonic development. Following this arrested period, oocytes resume meiosis in response to species-specific hormones, a process known as oocyte maturation, that precedes ovulation and fertilization. Involvement of endocrine and autocrine/paracrine factors and signaling events during maintenance of prophase I arrest, and resumption of meiosis is an area of active research. Studies in vertebrate and invertebrate model organisms have delineated the molecular determinants and signaling pathways that regulate oocyte maturation. Cell cycle regulators, such as cyclin-dependent kinase (CDK1), polo-like kinase (PLK1), Wee1/Myt1 kinase, and the phosphatase CDC25 play conserved roles during meiotic resumption. Extracellular signal-regulated kinase (ERK), on the other hand, while activated during oocyte maturation in all species, regulates both species-specific, as well as conserved events among different organisms. In this review, we synthesize the general signaling mechanisms and focus on conserved and distinct functions of ERK signaling pathway during oocyte maturation in mammals, non-mammalian vertebrates, and invertebrates such as Drosophila and Caenorhabditis elegans.
Topics: Animals; Caenorhabditis elegans; Cyclin-Dependent Kinases; Drosophila; Drosophila Proteins; Extracellular Signal-Regulated MAP Kinases; Female; Hormones; Mammals; Meiosis; Oocytes; Oogenesis; Phosphoric Monoester Hydrolases; Protein Kinases; Signal Transduction
PubMed: 35908193
DOI: 10.1002/mrd.23637 -
Nature Communications Aug 2022The ovarian reserve defines the female reproductive lifespan, which in humans spans decades due to robust maintenance of meiotic arrest in oocytes residing in primordial...
The ovarian reserve defines the female reproductive lifespan, which in humans spans decades due to robust maintenance of meiotic arrest in oocytes residing in primordial follicles. Epigenetic reprogramming, including DNA demethylation, accompanies meiotic entry, but the chromatin changes that underpin the generation and preservation of ovarian reserves are poorly defined. We report that the Polycomb Repressive Complex 1 (PRC1) establishes repressive chromatin states in perinatal mouse oocytes that directly suppress the gene expression program of meiotic prophase-I and thereby enable the transition to dictyate arrest. PRC1 dysfuction causes depletion of the ovarian reserve and leads to premature ovarian failure. Our study demonstrates a fundamental role for PRC1-mediated gene silencing in female reproductive lifespan, and reveals a critical window of epigenetic programming required to establish ovarian reserve.
Topics: Animals; Cell Cycle Proteins; Chromatin; Female; Gene Silencing; Humans; Meiosis; Mice; Ovarian Reserve; Polycomb Repressive Complex 1
PubMed: 35948547
DOI: 10.1038/s41467-022-31759-6 -
BioEssays : News and Reviews in... Oct 2023The ovarian reserve defines female reproductive lifespan, which in humans spans decades. The ovarian reserve consists of oocytes residing in primordial follicles...
The ovarian reserve defines female reproductive lifespan, which in humans spans decades. The ovarian reserve consists of oocytes residing in primordial follicles arrested in meiotic prophase I and is maintained independent of DNA replication and cell proliferation, thereby lacking stem cell-based maintenance. Largely unknown is how cellular states of the ovarian reserve are established and maintained for decades. Our recent study revealed that a distinct chromatin state is established during ovarian reserve formation in mice, uncovering a novel window of epigenetic programming in female germline development. We showed that an epigenetic regulator, Polycomb Repressive Complex 1 (PRC1), establishes a repressive chromatin state in perinatal mouse oocytes that is essential for prophase I-arrested oocytes to form the ovarian reserve. Here we discuss the biological roles and mechanisms underlying epigenetic programming in ovarian reserve formation, highlighting current knowledge gaps and emerging research areas in female reproductive biology.
Topics: Humans; Pregnancy; Female; Mice; Animals; Meiosis; Ovarian Reserve; Oocytes; Chromatin; Epigenesis, Genetic
PubMed: 37417392
DOI: 10.1002/bies.202300069 -
The Biochemical Journal Aug 2019The spatial configuration of chromatin is fundamental to ensure any given cell can fulfil its functional duties, from gene expression to specialised cellular division.... (Review)
Review
The spatial configuration of chromatin is fundamental to ensure any given cell can fulfil its functional duties, from gene expression to specialised cellular division. Significant technological innovations have facilitated further insights into the structure, function and regulation of three-dimensional chromatin organisation. To date, the vast majority of investigations into chromatin organisation have been conducted in interphase and mitotic cells leaving meiotic chromatin relatively unexplored. In combination, cytological and genome-wide contact frequency analyses in mammalian germ cells have recently demonstrated that large-scale chromatin structures in meiotic prophase I are reminiscent of the sequential loop arrays found in mitotic cells, although interphase-like segmentation of transcriptionally active and inactive regions are also evident along the length of chromosomes. Here, we discuss the similarities and differences of such large-scale chromatin architecture, between interphase, mitotic and meiotic cells, as well as their functional relevance and the proposed modulatory mechanisms which underlie them.
Topics: Animals; Chromatin; Germ Cells; Humans; Interphase; Meiosis; Mitosis
PubMed: 31383821
DOI: 10.1042/BCJ20180512 -
Frontiers in Cell and Developmental... 2023Meiosis is a specialized cell division that generates haploid gametes and is critical for successful sexual reproduction. During the extended meiotic prophase I,... (Review)
Review
Meiosis is a specialized cell division that generates haploid gametes and is critical for successful sexual reproduction. During the extended meiotic prophase I, homologous chromosomes progressively pair, synapse and desynapse. These chromosomal dynamics are tightly integrated with meiotic recombination (MR), during which programmed DNA double-strand breaks (DSBs) are formed and subsequently repaired. Consequently, parental chromosome arms reciprocally exchange, ultimately ensuring accurate homolog segregation and genetic diversity in the offspring. Surveillance mechanisms carefully monitor the MR and homologous chromosome synapsis during meiotic prophase I to avoid producing aberrant chromosomes and defective gametes. Errors in these critical processes would lead to aneuploidy and/or genetic instability. Studies of mutation in mouse models, coupled with advances in genomic technologies, lead us to more clearly understand how meiosis is controlled and how meiotic errors are linked to mammalian infertility. Here, we review the genetic regulations of these major meiotic events in mice and highlight our current understanding of their surveillance mechanisms. Furthermore, we summarize meiotic prophase genes, the mutations that activate the surveillance system leading to meiotic prophase arrest in mouse models, and their corresponding genetic variants identified in human infertile patients. Finally, we discuss their value for the diagnosis of causes of meiosis-based infertility in humans.
PubMed: 36910159
DOI: 10.3389/fcell.2023.1127440 -
Genes Nov 2021Regulation of transcriptional activity during meiosis depends on the interrelated processes of recombination and synapsis. In eutherian mammal spermatocytes,...
Regulation of transcriptional activity during meiosis depends on the interrelated processes of recombination and synapsis. In eutherian mammal spermatocytes, transcription levels change during prophase-I, being low at the onset of meiosis but highly increased from pachytene up to the end of diplotene. However, X and Y chromosomes, which usually present unsynapsed regions throughout prophase-I in male meiosis, undergo a specific pattern of transcriptional inactivation. The interdependence of synapsis and transcription has mainly been studied in mammals, basically in mouse, but our knowledge in other unrelated phylogenetically species is more limited. To gain new insights on this issue, here we analyzed the relationship between synapsis and transcription in spermatocytes of the grasshopper . Autosomal chromosomes of this species achieve complete synapsis; however, the single X sex chromosome remains always unsynapsed and behaves as a univalent. We studied transcription in meiosis by immunolabeling with RNA polymerase II phosphorylated at serine 2 and found that whereas autosomes are active from leptotene up to diakinesis, the X chromosome is inactive throughout meiosis. This inactivation is accompanied by the accumulation of, at least, two repressive epigenetic modifications: H3 methylated at lysine 9 and H2AX phosphorylated at serine 139. Furthermore, we identified that X chromosome inactivation occurs in premeiotic spermatogonia. Overall, our results indicate: (i) transcription regulation in spermatogenesis differs from the canonical pattern found in mammals and (ii) X chromosome inactivation is likely preceded by a process of heterochromatinization before the initiation of meiosis.
Topics: Animals; Chromosome Pairing; Epigenesis, Genetic; Female; Gene Silencing; Grasshoppers; Histones; Lysine; Male; Meiosis; Meiotic Prophase I; RNA Polymerase II; Spermatocytes; Spermatogenesis; X Chromosome; X Chromosome Inactivation; Y Chromosome
PubMed: 34946793
DOI: 10.3390/genes12121844 -
ELife Oct 2023In sexually reproducing organisms, germ cells faithfully transmit the genome to the next generation by forming haploid gametes, such as eggs and sperm. Although most...
In sexually reproducing organisms, germ cells faithfully transmit the genome to the next generation by forming haploid gametes, such as eggs and sperm. Although most meiotic proteins are conserved between eggs and sperm, many aspects of meiosis are sexually dimorphic, including the regulation of recombination. The synaptonemal complex (SC), a large ladder-like structure that forms between homologous chromosomes, is essential for regulating meiotic chromosome organization and promoting recombination. To assess whether sex-specific differences in the SC underpin sexually dimorphic aspects of meiosis, we examined SC central region proteins (known as SYP proteins) in oogenesis and spermatogenesis and uncovered sex-specific roles for the SYPs in regulating meiotic recombination. We find that SC composition, specifically SYP-2, SYP-3, SYP-5, and SYP-6, is regulated by sex-specific mechanisms throughout meiotic prophase I. During pachytene, both oocytes and spermatocytes differentially regulate the stability of SYP-2 and SYP-3 within an assembled SC. Further, we uncover that the relative amount of SYP-2 and SYP-3 within the SC is independently regulated in both a sex-specific and a recombination-dependent manner. Specifically, we find that SYP-2 regulates the early steps of recombination in both sexes, while SYP-3 controls the timing and positioning of crossover recombination events across the genomic landscape in only oocytes. Finally, we find that SYP-2 and SYP-3 dosage can influence the composition of the other SYPs in the SC via sex-specific mechanisms during pachytene. Taken together, we demonstrate dosage-dependent regulation of individual SC components with sex-specific functions in recombination. These sexual dimorphic features of the SC provide insights into how spermatogenesis and oogenesis adapted similar chromosome structures to differentially regulate and execute recombination.
Topics: Animals; Female; Male; Caenorhabditis elegans; Synaptonemal Complex; Meiosis; Semen; Caenorhabditis elegans Proteins
PubMed: 37796106
DOI: 10.7554/eLife.84538 -
BMC Biology Mar 2023Ovarian folliculogenesis is a tightly regulated process leading to the formation of functional oocytes and involving successive quality control mechanisms that monitor...
BACKGROUND
Ovarian folliculogenesis is a tightly regulated process leading to the formation of functional oocytes and involving successive quality control mechanisms that monitor chromosomal DNA integrity and meiotic recombination. A number of factors and mechanisms have been suggested to be involved in folliculogenesis and associated with premature ovarian insufficiency, including abnormal alternative splicing (AS) of pre-mRNAs. Serine/arginine-rich splicing factor 1 (SRSF1; previously SF2/ASF) is a pivotal posttranscriptional regulator of gene expression in various biological processes. However, the physiological roles and mechanism of SRSF1 action in mouse early-stage oocytes remain elusive. Here, we show that SRSF1 is essential for primordial follicle formation and number determination during meiotic prophase I.
RESULTS
The conditional knockout (cKO) of Srsf1 in mouse oocytes impairs primordial follicle formation and leads to primary ovarian insufficiency (POI). Oocyte-specific genes that regulate primordial follicle formation (e.g., Lhx8, Nobox, Sohlh1, Sohlh2, Figla, Kit, Jag1, and Rac1) are suppressed in newborn Stra8-GFPCre Srsf1 mouse ovaries. However, meiotic defects are the leading cause of abnormal primordial follicle formation. Immunofluorescence analyses suggest that failed synapsis and an inability to undergo recombination result in fewer homologous DNA crossovers (COs) in the Srsf1 cKO mouse ovaries. Moreover, SRSF1 directly binds and regulates the expression of the POI-related genes Six6os1 and Msh5 via AS to implement the meiotic prophase I program.
CONCLUSIONS
Altogether, our data reveal the critical role of an SRSF1-mediated posttranscriptional regulatory mechanism in the mouse oocyte meiotic prophase I program, providing a framework to elucidate the molecular mechanisms of the posttranscriptional network underlying primordial follicle formation.
Topics: Animals; Female; Mice; Alternative Splicing; Cell Cycle Proteins; DNA-Binding Proteins; Meiosis; Meiotic Prophase I; Oocytes; Ovary; Serine-Arginine Splicing Factors
PubMed: 36882745
DOI: 10.1186/s12915-023-01549-7 -
Frontiers in Cell and Developmental... 2023Actin is a multi-functional protein that is involved in numerous cellular processes including cytoskeleton regulation, cell migration, and cellular integrity. In these... (Review)
Review
Actin is a multi-functional protein that is involved in numerous cellular processes including cytoskeleton regulation, cell migration, and cellular integrity. In these processes, actin's role in respect to its structure, complex mechanical, and protein-binding properties has been studied primarily in the cytoplasmic and cellular membrane compartments. However, its role in somatic cell nuclei has recently become evident where it participates in transcription, chromatin remodeling, and DNA damage repair. What remains enigmatic is the involvement of nuclear actin in physiological processes that lead to the generation of germ cells, in general, and primary spermatocytes, in particular. Here, we will discuss the possible role and nuclear localization of actin during meiotic prophase I and its interaction with chromatin remodeling complexes, the latter being essential for the control of pairing of homologous chromosomes, cross-over formation, and recombination. It is our hope that this perspective article will extend the scope of actin's nuclear function in germ cells undergoing meiotic division.
PubMed: 38078006
DOI: 10.3389/fcell.2023.1295452 -
Cell Cycle (Georgetown, Tex.) Aug 2021A central player in meiotic chromosome dynamics is the conserved Polo-like kinase (PLK) family. PLKs are dynamically localized to distinct structures during meiotic... (Review)
Review
A central player in meiotic chromosome dynamics is the conserved Polo-like kinase (PLK) family. PLKs are dynamically localized to distinct structures during meiotic prophase and phosphorylate a diverse group of substrates to control homolog pairing, synapsis, and meiotic recombination. In a recent study, we uncovered the mechanisms that control the targeting of a meiosis-specific PLK-2 in . In early meiotic prophase, PLK-2 localizes to special chromosome regions known as pairing centers and drives homolog pairing and synapsis. PLK-2 then relocates to the synaptonemal complex (SC) after crossover designation and mediates chromosome remodeling required for homolog separation. What controls this intricate targeting of PLK-2 in space and time? We discuss recent findings and remaining questions for the future.
Topics: Animals; Binding Sites; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Chromosome Pairing; Chromosomes; Gene Expression Regulation; Meiosis; Meiotic Prophase I; Phosphorylation; Protein Binding; Protein Serine-Threonine Kinases; Signal Transduction
PubMed: 34266376
DOI: 10.1080/15384101.2021.1953232