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Genes May 2022During the early meiotic prophase, connections are established between chromosomes and cytoplasmic motors via a nuclear envelope bridge, known as a LINC (linker of... (Review)
Review
During the early meiotic prophase, connections are established between chromosomes and cytoplasmic motors via a nuclear envelope bridge, known as a LINC (linker of nucleoskeleton and cytoskeleton) complex. These widely conserved links can promote both chromosome and nuclear motions. Studies in diverse organisms have illuminated the molecular architecture of these connections, but important questions remain regarding how they contribute to meiotic processes. Here, we summarize the current knowledge in the field, outline the challenges in studying these chromosome dynamics, and highlight distinctive features that have been characterized in major model systems.
Topics: Chromosomes; Cytoskeleton; Meiosis; Microtubules; Nuclear Envelope
PubMed: 35627285
DOI: 10.3390/genes13050901 -
Cell Proliferation Apr 2024The successful progression of meiosis prophase I requires integrating information from the structural and molecular levels. In this study, we show that ZFP541 and KCTD19...
The successful progression of meiosis prophase I requires integrating information from the structural and molecular levels. In this study, we show that ZFP541 and KCTD19 work in the same genetic pathway to regulate the progression of male meiosis and thus fertility. The Zfp541 and/or Kctd19 knockout male mice show various structural and recombination defects including detached chromosome ends, aberrant localization of chromosome axis components and recombination proteins, and globally altered histone modifications. Further analyses on RNA-seq, ChIP-seq, and ATAC-seq data provide molecular evidence for the above defects and reveal that ZFP541/KCTD19 activates the expression of many genes by repressing several major transcription repressors. More importantly, we reveal an unexpected role of ZFP541/KCTD19 in directly modulating chromatin organization. These results suggest that ZFP541/KCTD19 simultaneously regulates the transcription cascade and chromatin organization to ensure the coordinated progression of multiple events at chromosome structural and biochemical levels during meiosis prophase I.
Topics: Animals; Mice; Male; Chromatin; Transcription Factors; Synaptonemal Complex; Protein Processing, Post-Translational; Meiosis; Chromosomal Proteins, Non-Histone
PubMed: 37921559
DOI: 10.1111/cpr.13567 -
FEBS Letters Oct 2019The primary function of cyclin-dependent kinases (CDKs) in complex with their activating cyclin partners is to promote mitotic division in somatic cells. This canonical... (Review)
Review
The primary function of cyclin-dependent kinases (CDKs) in complex with their activating cyclin partners is to promote mitotic division in somatic cells. This canonical cell cycle-associated activity is also crucial for fertility as it allows the proliferation and differentiation of stem cells within the reproductive organs to generate meiotically competent cells. Intriguingly, several CDKs exhibit meiosis-specific functions and are essential for the completion of the two reductional meiotic divisions required to generate haploid gametes. These meiosis-specific functions are mediated by both known CDK/cyclin complexes and meiosis-specific CDK-regulators and are important for a variety of processes during meiotic prophase. The majority of meiotic defects observed upon deletion of these proteins occur during the extended prophase I of the first meiotic division. Importantly a lack of redundancy is seen within the meiotic arrest phenotypes described for many of these proteins, suggesting intricate layers of cell cycle control are required for normal meiotic progression. Using the process of male germ cell development (spermatogenesis) as a reference, this review seeks to highlight the diverse roles of selected CDKs their activators, and their regulators during gametogenesis.
Topics: Animals; Cell Cycle Checkpoints; Cell Differentiation; Cell Proliferation; Cyclin-Dependent Kinases; Cyclins; Gene Expression Regulation; Haploidy; Male; Meiosis; Mice; Nuclear Proteins; Recombination, Genetic; Signal Transduction; Spermatogenesis; Spermatozoa; Stem Cells
PubMed: 31566717
DOI: 10.1002/1873-3468.13627 -
Science (New York, N.Y.) Jun 2022A hallmark of meiosis is chromosomal pairing, which requires telomere tethering and rotation on the nuclear envelope through microtubules, driving chromosome homology...
A hallmark of meiosis is chromosomal pairing, which requires telomere tethering and rotation on the nuclear envelope through microtubules, driving chromosome homology searches. Telomere pulling toward the centrosome forms the "zygotene chromosomal bouquet." Here, we identified the "zygotene cilium" in oocytes. This cilium provides a cable system for the bouquet machinery and extends throughout the germline cyst. Using zebrafish mutants and live manipulations, we demonstrate that the cilium anchors the centrosome to counterbalance telomere pulling. The cilium is essential for bouquet and synaptonemal complex formation, oogenesis, ovarian development, and fertility. Thus, a cilium represents a conserved player in zebrafish and mouse meiosis, which sheds light on reproductive aspects in ciliopathies and suggests that cilia can control chromosomal dynamics.
Topics: Animals; Centromere; Chromosome Pairing; Cilia; Female; Fertility; Mice; Morphogenesis; Oocytes; Oogenesis; Ovary; Telomere; Zebrafish
PubMed: 35549308
DOI: 10.1126/science.abh3104 -
International Journal of Biological... 2022About 10% of reproductive-aged couples suffer from infertility. However, the genetic causes of human infertility cases are largely unknown. Meiosis produces haploid... (Review)
Review
About 10% of reproductive-aged couples suffer from infertility. However, the genetic causes of human infertility cases are largely unknown. Meiosis produces haploid gametes for fertilization and errors in meiosis are associated with human infertility in both males and females. Successful meiosis relies on the assembly of the synaptonemal complex (SC) between paired homologous chromosomes during the meiotic prophase. The SC is ultrastructurally and functionally conserved, promoting inter-homologous recombination and crossover formation, thus critical for accurate meiotic chromosome segregation. With whole-genome/exome sequencing and mouse models, a list of mutations in SC coding genes has been linked to human infertility. Here we summarize those findings. We also analyzed SC gene variants present in the general population and presented complex interaction networks associated with SC components. Whether a combination of genetic variations and environmental factors causes human infertility demands further investigations.
Topics: Adult; Animals; Chromosome Segregation; Female; Germ Cells; Humans; Infertility; Male; Meiosis; Mice; Synaptonemal Complex
PubMed: 35342360
DOI: 10.7150/ijbs.67843 -
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 -
Biology of Reproduction Sep 2019Cyclins and cyclin-dependent kinases (CDKs) are key regulators of the cell cycle. Most of our understanding of their functions has been obtained from studies in... (Review)
Review
Cyclins and cyclin-dependent kinases (CDKs) are key regulators of the cell cycle. Most of our understanding of their functions has been obtained from studies in single-cell organisms and mitotically proliferating cultured cells. In mammals, there are more than 20 cyclins and 20 CDKs. Although genetic ablation studies in mice have shown that most of these factors are dispensable for viability and fertility, uncovering their functional redundancy, CCNA2, CCNB1, and CDK1 are essential for embryonic development. Cyclin/CDK complexes are known to regulate both mitotic and meiotic cell cycles. While some mechanisms are common to both types of cell divisions, meiosis has unique characteristics and requirements. During meiosis, DNA replication is followed by two successive rounds of cell division. In addition, mammalian germ cells experience a prolonged prophase I in males or a long period of arrest in prophase I in females. Therefore, cyclins and CDKs may have functions in meiosis distinct from their mitotic functions and indeed, meiosis-specific cyclins, CCNA1 and CCNB3, have been identified. Here, we describe recent advances in the field of cyclins and CDKs with a focus on meiosis and early embryogenesis.
Topics: Animals; Cyclin-Dependent Kinases; Cyclins; Embryo, Mammalian; Female; Gametogenesis; Germ Cells; Humans; Male; Mammals; Meiosis; Mice
PubMed: 31078132
DOI: 10.1093/biolre/ioz070 -
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 -
Frontiers in Cell and Developmental... 2021In female mammals, meiotic prophase one begins during fetal development. Oocytes transition through the prophase one substages consisting of leptotene, zygotene, and... (Review)
Review
In female mammals, meiotic prophase one begins during fetal development. Oocytes transition through the prophase one substages consisting of leptotene, zygotene, and pachytene, and are finally arrested at the diplotene substage, for months in mice and years in humans. After puberty, luteinizing hormone induces ovulation and meiotic resumption in a cohort of oocytes, driving the progression from meiotic prophase one to metaphase two. If fertilization occurs, the oocyte completes meiosis two followed by fusion with the sperm nucleus and preparation for zygotic divisions; otherwise, it is passed into the uterus and degenerates. Specifically in the mouse, oocytes enter meiosis at 13.5 days post coitum. As meiotic prophase one proceeds, chromosomes find their homologous partner, synapse, exchange genetic material between homologs and then begin to separate, remaining connected at recombination sites. At postnatal day 5, most of the oocytes have reached the late diplotene (or dictyate) substage of prophase one where they remain arrested until ovulation. This review focuses on events and mechanisms controlling the progression through meiotic prophase one, which include recombination, synapsis and control by signaling pathways. These events are prerequisites for proper chromosome segregation in meiotic divisions; and if they go awry, chromosomes mis-segregate resulting in aneuploidy. Therefore, elucidating the mechanisms regulating meiotic progression is important to provide a foundation for developing improved treatments of female infertility.
PubMed: 34095134
DOI: 10.3389/fcell.2021.667306 -
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