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Genetics Mar 2021In most species that reproduce sexually, successful gametogenesis requires recombination during meiosis. The number and placement of crossovers (COs) vary among...
In most species that reproduce sexually, successful gametogenesis requires recombination during meiosis. The number and placement of crossovers (COs) vary among individuals, with females and males often presenting the most striking contrasts. Despite the recognition that the sexes recombine at different rates (heterochiasmy), existing data fail to answer the question of whether patterns of genetic variation in recombination rate are similar in the two sexes. To fill this gap, we measured the genome-wide recombination rate in both sexes from a panel of wild-derived inbred strains from multiple subspecies of house mice (Mus musculus) and from a few additional species of Mus. To directly compare recombination rates in females and males from the same genetic backgrounds, we applied established methods based on immunolocalization of recombination proteins to inbred strains. Our results reveal discordant patterns of genetic variation in the two sexes. Whereas male genome-wide recombination rates vary substantially among strains, female recombination rates measured in the same strains are more static. The direction of heterochiasmy varies within two subspecies, Mus musculus molossinus and Mus musculus musculus. The direction of sex differences in the length of the synaptonemal complex and CO positions is consistent across strains and does not track sex differences in genome-wide recombination rate. In males, contrasts between strains with high recombination rate and strains with low recombination rate suggest more recombination is associated with stronger CO interference and more double-strand breaks. The sex-specific patterns of genetic variation we report underscore the importance of incorporating sex differences into recombination research.
Topics: Animals; Crossing Over, Genetic; Female; Genetic Background; Genetic Variation; Genome; Male; Mice; Sex Factors; Species Specificity; Synaptonemal Complex
PubMed: 33683358
DOI: 10.1093/genetics/iyaa019 -
Journal of Cell Science Aug 2020During prophase I of meiosis, homologous chromosomes pair, synapse and exchange their genetic material through reciprocal homologous recombination, a phenomenon... (Review)
Review
During prophase I of meiosis, homologous chromosomes pair, synapse and exchange their genetic material through reciprocal homologous recombination, a phenomenon essential for faithful chromosome segregation. Partial sequence identity between non-homologous and heterologous chromosomes can also lead to recombination (ectopic recombination), a highly deleterious process that rapidly compromises genome integrity. To avoid ectopic exchange, homology recognition must be extended from the narrow position of a crossover-competent double-strand break to the entire chromosome. Here, we review advances on chromosome behaviour during meiotic prophase I in higher plants, by integrating centromere- and telomere dynamics driven by cytoskeletal motor proteins, into the processes of homologue pairing, synapsis and recombination. Centromere-centromere associations and the gathering of telomeres at the onset of meiosis at opposite nuclear poles create a spatially organised and restricted nuclear state in which homologous DNA interactions are favoured but ectopic interactions also occur. The release and dispersion of centromeres from the nuclear periphery increases the motility of chromosome arms, allowing meiosis-specific movements that disrupt ectopic interactions. Subsequent expansion of interstitial synapsis from numerous homologous interactions further corrects ectopic interactions. Movement and organisation of chromosomes, thus, evolved to facilitate the pairing process, and can be modulated by distinct stages of chromatin associations at the nuclear envelope and their collective release.
Topics: Centromere; Chromosome Pairing; Chromosome Segregation; Meiosis; Nuclear Envelope; Telomere
PubMed: 32788229
DOI: 10.1242/jcs.243667 -
Cells Dec 2022Human Perrault syndrome (PRLTS) is autosomal, recessively inherited, and characterized by ovarian insufficiency with hearing loss. Among the genetic causes are mutations...
Human Perrault syndrome (PRLTS) is autosomal, recessively inherited, and characterized by ovarian insufficiency with hearing loss. Among the genetic causes are mutations of matrix peptidase CLPP, which trigger additional azoospermia. Here, we analyzed the impact of CLPP deficiency on male mouse meiosis stages. Histology, immunocytology, different OMICS and biochemical approaches, and RT-qPCR were employed in CLPP-null mouse testis. Meiotic chromosome pairing and synapsis proceeded normally. However, the foci number of the crossover marker MLH1 was slightly reduced, and foci persisted in diplotene, most likely due to premature desynapsis, associated with an accumulation of the DNA damage marker γH2AX. No meiotic M-phase cells were detected. Proteome profiles identified strong deficits of proteins involved in male meiotic prophase (HSPA2, SHCBP1L, DMRT7, and HSF5), versus an accumulation of AURKAIP1. Histone H3 cleavage, mtDNA extrusion, and cGAMP increase suggested innate immunity activation. However, the deletion of downstream STING/IFNAR failed to alleviate pathology. As markers of underlying mitochondrial pathology, we observed an accumulation of PRLTS proteins ERAL1, PEO1, and HARS2. We propose that the loss of CLPP leads to the extrusion of mitochondrial nucleotide-binding proteins to cytosol and nucleus, affecting late meiotic prophase progression, and causing cell death prior to M-phase entry. This phenotype is more severe than in mito-mice or mutator-mice.
Topics: Male; Humans; Animals; Mice; Meiosis; Testis; Meiotic Prophase I; Mutation; Mitochondrial Proteins; Mitochondria; Amino Acyl-tRNA Synthetases; Endopeptidase Clp
PubMed: 36611846
DOI: 10.3390/cells12010052 -
Nature Communications Oct 2021PIWI-interacting small RNAs (piRNAs) protect the germline genome and are essential for fertility. piRNAs originate from transposable element (TE) RNAs, long non-coding...
PIWI-interacting small RNAs (piRNAs) protect the germline genome and are essential for fertility. piRNAs originate from transposable element (TE) RNAs, long non-coding RNAs, or 3´ untranslated regions (3´UTRs) of protein-coding messenger genes, with the last being the least characterized of the three piRNA classes. Here, we demonstrate that the precursors of 3´UTR piRNAs are full-length mRNAs and that post-termination 80S ribosomes guide piRNA production on 3´UTRs in mice and chickens. At the pachytene stage, when other co-translational RNA surveillance pathways are sequestered, piRNA biogenesis degrades mRNAs right after pioneer rounds of translation and fine-tunes protein production from mRNAs. Although 3´UTR piRNA precursor mRNAs code for distinct proteins in mice and chickens, they all harbor embedded TEs and produce piRNAs that cleave TEs. Altogether, we discover a function of the piRNA pathway in fine-tuning protein production and reveal a conserved piRNA biogenesis mechanism that recognizes translating RNAs in amniotes.
Topics: 3' Untranslated Regions; Animals; Base Sequence; Chickens; DNA Transposable Elements; Fertility; Gene Expression Regulation; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pachytene Stage; Protein Biosynthesis; RNA, Small Interfering; Ribosomes; Spermatogenesis; Testis
PubMed: 34645830
DOI: 10.1038/s41467-021-26233-8 -
BioRxiv : the Preprint Server For... Jul 2023The centromere is an epigenetic mark that is a loading site for the kinetochore during meiosis and mitosis. This mark is characterized by the H3 variant CENP-A, known as...
The centromere is an epigenetic mark that is a loading site for the kinetochore during meiosis and mitosis. This mark is characterized by the H3 variant CENP-A, known as CID in . In , CENP-C is critical for maintaining CID at the centromeres and directly recruits outer kinetochore proteins after nuclear envelope break down. It is not known, however, if these two functions require the same CENP-C molecules. Furthermore, in and many other metazoan oocytes, centromere maintenance and kinetochore assembly are separated by an extended prophase. Consistent with studies in mammals, CID is relatively stable and does not need to be expressed during prophase to remain at high levels in metaphase I of meiosis. Expression of CID during prophase can even be deleterious, causing ectopic localization to non-centromeric chromatin, abnormal meiosis and sterility. In contrast to CID, maintaining high levels of CENP-C requires expression during prophase. Confirming the importance of this loading, we found CENP-C prophase loading is required for multiple meiotic functions. In early meiotic prophase, CENP-C loading is required for sister centromere cohesion and centromere clustering. In late meiotic prophase, CENP-C loading is required to recruit kinetochore proteins. CENP-C is one of the few proteins identified in which expression during prophase is required for meiotic chromosome segregation. An implication of these results is that the failure to maintain recruitment of CENP-C during the extended prophase in oocytes would result in chromosome segregation errors in oocytes.
PubMed: 36993339
DOI: 10.1101/2023.03.13.532437 -
European Journal of Cell Biology Apr 2022In mammalian females, oocytes are stored in the ovary and meiosis is arrested at the diplotene stage of prophase I. When females reach puberty oocytes are selectively...
In mammalian females, oocytes are stored in the ovary and meiosis is arrested at the diplotene stage of prophase I. When females reach puberty oocytes are selectively recruited in cycles to grow, overcome the meiotic arrest, complete the first meiotic division and become mature (ready for fertilization). At a molecular level, the master regulator of prophase I arrest and meiotic resumption is the maturation-promoting factor (MPF) complex, formed by the active form of cyclin dependent kinase 1 (CDK1) and Cyclin B1. However, we still do not have complete information regarding the factors implicated in MPF activation. In this study we document that out of three mammalian serum-glucocorticoid kinase proteins (SGK1, SGK2, SGK3), mouse oocytes express only SGK1 with a phosphorylated (active) form dominantly localized in the nucleoplasm. Further, suppression of SGK1 activity in oocytes results in decreased CDK1 activation via the phosphatase cell division cycle 25B (CDC25B), consequently delaying or inhibiting nuclear envelope breakdown. Expression of exogenous constitutively active CDK1 can rescue the phenotype induced by SGK1 inhibition. These findings bring new insights into the molecular pathways acting upstream of MPF and a better understanding of meiotic resumption control by presenting a new key player SGK1 in mammalian oocytes.
Topics: Animals; Cell Cycle Checkpoints; Female; Immediate-Early Proteins; Mammals; Maturation-Promoting Factor; Meiosis; Meiotic Prophase I; Mice; Oocytes; Protein Serine-Threonine Kinases
PubMed: 35240557
DOI: 10.1016/j.ejcb.2022.151210 -
Cells Feb 2022DNA damage in cells can occur physiologically or may be induced by exogenous factors. Genotoxic damage may cause cancer, ageing, serious developmental diseases and... (Review)
Review
DNA damage in cells can occur physiologically or may be induced by exogenous factors. Genotoxic damage may cause cancer, ageing, serious developmental diseases and anomalies. If the damage occurs in the germline, it can potentially lead to infertility or chromosomal and genetic aberrations in the developing embryo. Mammalian oocytes, the female germ cells, are produced before birth, remaining arrested at the prophase stage of meiosis over a long period of time. During this extensive state of arrest the oocyte may be exposed to different DNA-damaging insults for months, years or even decades. Therefore, it is of great importance to understand how these cells respond to DNA damage. In this review, we summarize the most recent developments in the understanding of the DNA damage response mechanisms that function in fully grown mammalian oocytes.
Topics: Animals; DNA Damage; Female; Infertility; Mammals; Meiosis; Oocytes
PubMed: 35269420
DOI: 10.3390/cells11050798 -
The Journal of Cell Biology Feb 2024During meiosis, cohesin and meiosis-specific proteins organize chromatin into an axis-loop architecture, coordinating homologous synapsis, recombination, and ordered...
During meiosis, cohesin and meiosis-specific proteins organize chromatin into an axis-loop architecture, coordinating homologous synapsis, recombination, and ordered chromosome segregation. However, how the meiotic chromosome axis is assembled and differentiated with meiotic progression remains elusive. Here, we explore the dynamic recruitment of two long arms of the bivalent proteins, LAB-1 and LAB-2, in Caenorhabditis elegans. LAB proteins directly interact with the axis core HORMA complexes and weak interactions contribute to their recruitment. LAB proteins phase separate in vitro, and this capacity is promoted by HORMA complexes. During early prophase, synapsis oppositely regulates the axis enrichment of LAB proteins. After the pachytene exit, LAB proteins switch from a reciprocal localization pattern to a colocalization pattern, and the normal dynamic pattern of LAB proteins is altered in meiotic mutants. We propose that LAB recruitment senses axis differentiation, and phase separation of meiotic structures helps subdomain establishment and accurate segregation of the chromosomes.
Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Cell Cycle Proteins; Chromosome Pairing; Chromosome Segregation; Chromosomes; Meiosis; Chromosomal Proteins, Non-Histone
PubMed: 38010234
DOI: 10.1083/jcb.202212035 -
Frontiers in Plant Science 2020In flowering plants, successful germinal cell development and meiotic recombination depend upon a combination of environmental and genetic factors. To gain insights into...
In flowering plants, successful germinal cell development and meiotic recombination depend upon a combination of environmental and genetic factors. To gain insights into this specialized reproductive development program we used short- and long-read RNA-sequencing (RNA-seq) to study the temporal dynamics of transcript abundance in immuno-cytologically staged barley () anthers and meiocytes. We show that the most significant transcriptional changes in anthers occur at the transition from pre-meiosis to leptotene-zygotene, which is followed by increasingly stable transcript abundance throughout prophase I into metaphase I-tetrad. Our analysis reveals that the pre-meiotic anthers are enriched in long non-coding RNAs (lncRNAs) and that entry to meiosis is characterized by their robust and significant down regulation. Intriguingly, only 24% of a collection of putative meiotic gene orthologs showed differential transcript abundance in at least one stage or tissue comparison. Argonautes, E3 ubiquitin ligases, and lys48 specific de-ubiquitinating enzymes were enriched in prophase I meiocyte samples. These developmental, time-resolved transcriptomes demonstrate remarkable stability in transcript abundance in meiocytes throughout prophase I after the initial and substantial reprogramming at meiosis entry and the complexity of the regulatory networks involved in early meiotic processes.
PubMed: 33510760
DOI: 10.3389/fpls.2020.619404 -
Nature Structural & Molecular Biology Feb 2023In meiosis, a supramolecular protein structure, the synaptonemal complex (SC), assembles between homologous chromosomes to facilitate their recombination. Mammalian SC...
In meiosis, a supramolecular protein structure, the synaptonemal complex (SC), assembles between homologous chromosomes to facilitate their recombination. Mammalian SC formation is thought to involve hierarchical zipper-like assembly of an SYCP1 protein lattice that recruits stabilizing central element (CE) proteins as it extends. Here we combine biochemical approaches with separation-of-function mutagenesis in mice to show that, rather than stabilizing the SYCP1 lattice, the CE protein SYCE3 actively remodels this structure during synapsis. We find that SYCP1 tetramers undergo conformational change into 2:1 heterotrimers on SYCE3 binding, removing their assembly interfaces and disrupting the SYCP1 lattice. SYCE3 then establishes a new lattice by its self-assembly mimicking the role of the disrupted interface in tethering together SYCP1 dimers. SYCE3 also interacts with CE complexes SYCE1-SIX6OS1 and SYCE2-TEX12, providing a mechanism for their recruitment. Thus, SYCE3 remodels the SYCP1 lattice into a CE-binding integrated SYCP1-SYCE3 lattice to achieve long-range synapsis by a mature SC.
Topics: Animals; Mice; Chromosomal Proteins, Non-Histone; Chromosome Pairing; DNA-Binding Proteins; Mammals; Meiosis; Nuclear Proteins; Synaptonemal Complex
PubMed: 36635604
DOI: 10.1038/s41594-022-00909-1