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PLoS Genetics Apr 2017The meiosis-specific chromosomal events of homolog pairing, synapsis, and recombination occur over an extended meiotic prophase I that is many times longer than prophase...
The meiosis-specific chromosomal events of homolog pairing, synapsis, and recombination occur over an extended meiotic prophase I that is many times longer than prophase of mitosis. Here we show that, in mice, maintenance of an extended meiotic prophase I requires the gene Meioc, a germ-cell specific factor conserved in most metazoans. In mice, Meioc is expressed in male and female germ cells upon initiation of and throughout meiotic prophase I. Mouse germ cells lacking Meioc initiate meiosis: they undergo pre-meiotic DNA replication, they express proteins involved in synapsis and recombination, and a subset of cells progress as far as the zygotene stage of prophase I. However, cells in early meiotic prophase-as early as the preleptotene stage-proceed to condense their chromosomes and assemble a spindle, as if having progressed to metaphase. Meioc-deficient spermatocytes that have initiated synapsis mis-express CYCLIN A2, which is normally expressed in mitotic spermatogonia, suggesting a failure to properly transition to a meiotic cell cycle program. MEIOC interacts with YTHDC2, and the two proteins pull-down an overlapping set of mitosis-associated transcripts. We conclude that when the meiotic chromosomal program is initiated, Meioc is simultaneously induced so as to extend meiotic prophase. Specifically, MEIOC, together with YTHDC2, promotes a meiotic (as opposed to mitotic) cell cycle program via post-transcriptional control of their target transcripts.
Topics: Animals; Cell Cycle Proteins; Chromosome Pairing; Cyclin A2; Gene Expression Regulation, Developmental; Male; Meiosis; Mice; Mitosis; Prophase; RNA-Binding Proteins; Spermatocytes; Spermatogenesis; Spermatogonia
PubMed: 28380054
DOI: 10.1371/journal.pgen.1006704 -
Communications Biology Jul 2023The nucleus plays a central role in several key cellular processes, including chromosome organisation, DNA replication and gene transcription. Recent work suggests an...
The nucleus plays a central role in several key cellular processes, including chromosome organisation, DNA replication and gene transcription. Recent work suggests an association between nuclear mechanics and cell-cycle progression, but many aspects of this connection remain unexplored. Here, by monitoring nuclear shape fluctuations at different cell cycle stages, we uncover increasing inward fluctuations in late G2 and in early prophase, which are initially transient, but develop into instabilities when approaching the nuclear-envelope breakdown. We demonstrate that such deformations correlate with chromatin condensation by perturbing both the chromatin and the cytoskeletal structures. We propose that the contrasting forces between an extensile stress and centripetal pulling from chromatin condensation could mechanically link chromosome condensation with nuclear-envelope breakdown, two main nuclear processes occurring during mitosis.
Topics: Humans; Chromatin; Cell Nucleus; Mitosis; Prophase; Research Personnel
PubMed: 37438411
DOI: 10.1038/s42003-023-05074-9 -
Current Biology : CB Nov 2020Checkpoint cascades link cell cycle progression with essential chromosomal processes. During meiotic prophase, recombination and chromosome synapsis are monitored by...
Checkpoint cascades link cell cycle progression with essential chromosomal processes. During meiotic prophase, recombination and chromosome synapsis are monitored by what are considered distinct checkpoints. In budding yeast, cells that lack the AAA+ ATPase Pch2 show an impaired cell cycle arrest in response to synapsis defects. However, unperturbed pch2Δ cells are delayed in meiotic prophase, suggesting paradoxical roles for Pch2 in cell cycle progression. Here, we provide insight into the checkpoint roles of Pch2 and its connection to Hop1, a HORMA domain-containing client protein. Contrary to current understanding, we find that Pch2 (together with Hop1) is crucial for checkpoint function in response to both recombination and synapsis defects, thus revealing a shared meiotic checkpoint cascade. Meiotic checkpoint responses are transduced by DNA break-dependent phosphorylation of Hop1. Based on our data and on the described effect of Pch2 on HORMA topology, we propose that Pch2 promotes checkpoint proficiency by catalyzing the availability of signaling-competent Hop1. Conversely, we demonstrate that Pch2 can act as a checkpoint silencer, also in the face of persistent DNA repair defects. We establish a framework in which Pch2 and Hop1 form a homeostatic module that governs general meiotic checkpoint function. We show that this module can-depending on the cellular context-fuel or extinguish meiotic checkpoint function, which explains the contradictory roles of Pch2 in cell cycle control. Within the meiotic prophase checkpoint, the Pch2-Hop1 module thus operates analogous to the Pch2/TRIP13-Mad2 module in the spindle assembly checkpoint that monitors chromosome segregation.
Topics: Chromosome Segregation; DNA-Binding Proteins; Feedback, Physiological; M Phase Cell Cycle Checkpoints; Nuclear Proteins; Phosphorylation; Prophase; Protein Multimerization; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Spindle Apparatus; Synaptonemal Complex
PubMed: 32916108
DOI: 10.1016/j.cub.2020.08.064 -
Cytogenetics and Cell Genetics 1986Extensive experience with the analysis of human prophase chromosomes and studies into the complexity of prophase banding patterns have suggested that at least some...
Extensive experience with the analysis of human prophase chromosomes and studies into the complexity of prophase banding patterns have suggested that at least some prophase chromosomal segments can be accurately identified and characterized independently of the morphology of the chromosome as a whole. The feasibility of identifying and analyzing specified prophase chromosome segments was thus investigated as an alternative approach to prophase chromosome analysis based on whole-chromosome recognition. Through the use of prophase idiograms at the 850-band stage (Francke, 1981) and a systematic comparison system, we have demonstrated that it is possible to divide the 24 human prophase idiograms into a set of 94 unique band sequences, each of which has a banding pattern that is recognizable and distinct from any other nonhomologous chromosome portion. The use of a unique band sequence approach in prophase chromosome analysis is expected to increase efficiency and sensitivity through more effective use of available banding information.
Topics: Chromosome Banding; Genetic Markers; Humans; Karyotyping; Prophase; Templates, Genetic
PubMed: 3460743
DOI: 10.1159/000132267 -
Annual Review of Genetics Nov 2021The specialized two-stage meiotic cell division program halves a cell's chromosome complement in preparation for sexual reproduction. This reduction in ploidy requires... (Review)
Review
The specialized two-stage meiotic cell division program halves a cell's chromosome complement in preparation for sexual reproduction. This reduction in ploidy requires that in meiotic prophase, each pair of homologous chromosomes (homologs) identify one another and form physical links through DNA recombination. Here, we review recent advances in understanding the complex morphological changes that chromosomes undergo during meiotic prophase to promote homolog identification and crossing over. We focus on the structural maintenance of chromosomes (SMC) family cohesin complexes and the meiotic chromosome axis, which together organize chromosomes and promote recombination. We then discuss the architecture and dynamics of the conserved synaptonemal complex (SC), which assembles between homologs and mediates local and global feedback to ensure high fidelity in meiotic recombination. Finally, we discuss exciting new advances, including mechanisms for boosting recombination on particular chromosomes or chromosomal domains and the implications of a new liquid crystal model for SC assembly and structure.
Topics: Chromosome Pairing; Chromosomes; Homologous Recombination; Meiosis; Synaptonemal Complex
PubMed: 34530636
DOI: 10.1146/annurev-genet-071719-020235 -
Experimental Cell Research Oct 2019A typical nucleolus structure is shaped by three components. A meshwork of fine fibers forming the fibrillar center (FC) is surrounded by densely packed fibers forming...
A typical nucleolus structure is shaped by three components. A meshwork of fine fibers forming the fibrillar center (FC) is surrounded by densely packed fibers forming the dense fibrillar component (DFC). Meanwhile, wrapping the FC and DFC is the granular component (GC). During the mitotic prophase, the nucleolus undergoes disassembling of its components. On the contrary, throughout the first meiotic prophase that occurs in the cells of the germ line, small nucleoli are assembled into one nucleolus by the end of the prophase. These nucleoli are transcriptionally active, suggesting that they are fully functional. Electron microscopy analysis has suggested that these nucleoli display their three main components but a typical organization has not been observed. Here, by immunolabeling and electron microscopy, we show that the nucleolus has its three main components. The GC is interlaced with the DFC and is not as well defined as previously thought during leptotene and zygotene stage.
Topics: Animals; Cell Nucleolus; Male; Meiosis; Microscopy, Electron; Prophase; Rats; Spermatocytes; Synaptonemal Complex; Testis
PubMed: 31454492
DOI: 10.1016/j.yexcr.2019.111587 -
Reproduction (Cambridge, England) Jan 2016Binding of 17β-estradiol (E2) to novel G-protein coupled receptor, Gper1, promotes intra-oocyte adenylyl cyclase activity and transactivates epidermal growth factor...
Binding of 17β-estradiol (E2) to novel G-protein coupled receptor, Gper1, promotes intra-oocyte adenylyl cyclase activity and transactivates epidermal growth factor receptor to ensure prophase-I arrest. Although involvement of either membrane progestin receptor (mPR) or Igf system has been implicated in regulation of meiosis resumption, possibility of concurrent activation and potential synergism between 17α,20β-dihydroxy-4-pregnen-3-one (DHP)- and Igf-mediated signalling cascades in alleviating E2 inhibition of oocyte maturation (OM) has not been investigated. Here using zebrafish (Danio rerio) defolliculated oocytes, we examined the effect of DHP and Igf1, either alone or in combination, in presence or absence of E2, on OM in vitro. While priming of denuded oocytes with E2 blocked spontaneous maturation, co-treatment with DHP (3 nM) and Igf1 (10 nM), but not alone, reversed E2 inhibition and promoted a robust increase in germinal vesicle breakdown (GVBD). Although stimulation with either Igf1 or DHP promoted Akt phosphorylation, pharmacological inhibition of PI3K/Akt signalling prevented Igf1-induced GVBD but delayed DHP action till 4-5 h of incubation. Moreover, high intra-oocyte cAMP attenuates both DHP and Igf1-mediated OM and co-stimulation with DHP and Igf1 could effectively reverse E2 action on PKA phosphorylation. Interestingly, data from in vivo studies reveal that heightened expression of igf1, igf3 transcripts in intact follicles corresponded well with elevated phosphorylation of Igf1r and Akt, mPRa immunoreactivity, PKA inhibition and accelerated GVBD response just prior to ovulation. This indicates potential synergism between maturational steroid and Igf1 which might have physiological relevance in overcoming E2 inhibition of meiosis resumption in zebrafish oocytes.
Topics: Animals; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Drug Synergism; Estradiol; Female; Hydroxyprogesterones; Oocytes; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Prophase; Signal Transduction; Somatomedins; Zebrafish; Zebrafish Proteins
PubMed: 26500283
DOI: 10.1530/REP-15-0389 -
Current Topics in Developmental Biology 2023Sexually reproducing organisms produce haploid gametes through meiotic cell division, during which a single round of DNA replication is followed by two consecutive... (Review)
Review
Sexually reproducing organisms produce haploid gametes through meiotic cell division, during which a single round of DNA replication is followed by two consecutive chromosome segregation. A series of meiosis-specific events take place during the meiotic prophase to ensure successful chromosome segregation. These events include programmed DNA double-strand break formation, chromosome movement driven by cytoplasmic forces, homologous pairing, synaptonemal complex installation, and inter-homolog crossover formation. Phase separation has emerged as a key principle controlling cellular biomolecular material organization and biological processes. Recent studies have revealed the involvements of phase separation in assembling meiotic chromosome-associated structures. Here we review and discuss how phase separation may participate in meiotic chromosome dynamics and propose that it may provide opportunities to understand the mysteries in meiotic regulations.
Topics: Meiosis; Synaptonemal Complex; DNA Breaks, Double-Stranded; Chromosome Segregation
PubMed: 36681478
DOI: 10.1016/bs.ctdb.2022.04.004 -
Genes Apr 2022During meiosis, homologous chromosomes must recognize, pair, and recombine with one another to ensure the formation of inter-homologue crossover events, which, together... (Review)
Review
During meiosis, homologous chromosomes must recognize, pair, and recombine with one another to ensure the formation of inter-homologue crossover events, which, together with sister chromatid cohesion, promote correct chromosome orientation on the first meiotic spindle. Crossover formation requires the assembly of axial elements, proteinaceous structures that assemble along the length of each chromosome during early meiosis, as well as checkpoint mechanisms that control meiotic progression by monitoring pairing and recombination intermediates. A conserved family of proteins defined by the presence of a HORMA (HOp1, Rev7, MAd2) domain, referred to as HORMADs, associate with axial elements to control key events of meiotic prophase. The highly conserved HORMA domain comprises a flexible safety belt sequence, enabling it to adopt at least two of the following protein conformations: one closed, where the safety belt encircles a small peptide motif present within an interacting protein, causing its topological entrapment, and the other open, where the safety belt is reorganized and no interactor is trapped. Although functional studies in multiple organisms have revealed that HORMADs are crucial regulators of meiosis, the mechanisms by which HORMADs implement key meiotic events remain poorly understood. In this review, we summarize protein complexes formed by HORMADs, discuss their roles during meiosis in different organisms, draw comparisons to better characterize non-meiotic HORMADs (MAD2 and REV7), and highlight possible areas for future research.
Topics: Cell Cycle Proteins; Chromosome Segregation; Meiosis; Spindle Apparatus; Synaptonemal Complex
PubMed: 35627161
DOI: 10.3390/genes13050777 -
Current Biology : CB Oct 2018The conserved factor Shugoshin is dispensable in C. elegans for the two-step loss of sister chromatid cohesion that directs the proper segregation of meiotic...
The conserved factor Shugoshin is dispensable in C. elegans for the two-step loss of sister chromatid cohesion that directs the proper segregation of meiotic chromosomes. We show that the C. elegans ortholog of Shugoshin, SGO-1, is required for checkpoint activity in meiotic prophase. This role in checkpoint function is similar to that of conserved proteins that structure meiotic chromosome axes. Indeed, null sgo-1 mutants exhibit additional phenotypes similar to that of a partial loss-of-function allele of the axis component, HTP-3: premature synaptonemal complex disassembly, the activation of alternate DNA repair pathways, and an inability to recruit a conserved effector of the DNA damage pathway, HUS-1. SGO-1 localizes to pre-meiotic nuclei when HTP-3 is present but not yet loaded onto chromosome axes and genetically interacts with a central component of the cohesin complex, SMC-3, suggesting that it contributes to meiotic chromosome metabolism early in meiosis by regulating cohesin. We propose that SGO-1 acts during pre-meiotic replication to ensure fully functional meiotic chromosome architecture, rendering these chromosomes competent for checkpoint activity and normal progression of meiotic recombination. Given that most research on Shugoshin has focused on its regulation of sister chromatid cohesion during chromosome segregation, this novel role may be conserved but previously uncharacterized in other organisms. Further, our findings expand the repertoire of Shugoshin's functions beyond coordinating regulatory activities at the centromere.
Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Cell Cycle Checkpoints; Cell Cycle Proteins; Chromosomal Proteins, Non-Histone; Chromosome Segregation; Meiosis; Prophase; Synaptonemal Complex; Cohesins
PubMed: 30293721
DOI: 10.1016/j.cub.2018.08.026