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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 -
BioRxiv : the Preprint Server For... Nov 2023Meiotic sex chromosome inactivation (MSCI) is a critical feature of meiotic prophase I progression in males. While the ATR kinase and its activator TOPBP1 are key...
Meiotic sex chromosome inactivation (MSCI) is a critical feature of meiotic prophase I progression in males. While the ATR kinase and its activator TOPBP1 are key drivers of MSCI within the specialized sex body (SB) domain of the nucleus, how they promote silencing remains unclear given their multifaceted meiotic functions that also include DNA repair, chromosome synapsis and SB formation. Here we report a novel mutant mouse harboring mutations in the TOPBP1-BRCT5 domain. males are infertile, with impaired MSCI despite displaying grossly normal events of early prophase I, including synapsis and SB formation. Specific ATR-dependent events are disrupted including phosphorylation and localization of the RNA:DNA helicase Senataxin. spermatocytes initiate, but cannot maintain ongoing, MSCI. These findings reveal a non-canonical role for the ATR-TOPBP1 signaling axis in MSCI dynamics at advanced stages in pachynema and establish the first mouse mutant that separates ATR signaling and MSCI from SB formation.
PubMed: 37398453
DOI: 10.1101/2023.05.31.543071 -
Chromatin remodeler CHD8 is required for spermatogonial proliferation and early meiotic progression.Nucleic Acids Research Apr 2024Meiosis is a key step during germ cell differentiation, accompanied by the activation of thousands of genes through germline-specific chromatin reorganization. The...
Meiosis is a key step during germ cell differentiation, accompanied by the activation of thousands of genes through germline-specific chromatin reorganization. The chromatin remodeling mechanisms underpinning early meiotic stages remain poorly understood. Here we focus on the function of one of the major autism genes, CHD8, in spermatogenesis, based on the epidemiological association between autism and low fertility rates. Specific ablation of Chd8 in germ cells results in gradual depletion of undifferentiated spermatogonia and the failure of meiotic double-strand break (DSB) formation, leading to meiotic prophase I arrest and cell death. Transcriptional analyses demonstrate that CHD8 is required for extensive activation of spermatogenic genes in spermatogonia, necessary for spermatogonial proliferation and meiosis. CHD8 directly binds and regulates genes crucial for meiosis, including H3K4me3 histone methyltransferase genes, meiotic cohesin genes, HORMA domain-containing genes, synaptonemal complex genes, and DNA damage response genes. We infer that CHD8 contributes to meiotic DSB formation and subsequent meiotic progression through combined regulation of these meiosis-related genes. Our study uncovers an essential role of CHD8 in the proliferation of undifferentiated spermatogonia and the successful progression of meiotic prophase I.
Topics: Male; Cell Proliferation; Chromatin; Meiosis; Spermatogenesis; Spermatogonia; Animals; Mice
PubMed: 38224953
DOI: 10.1093/nar/gkad1256 -
Molecular Cell Sep 2020A long-standing conundrum is how mitotic chromosomes can compact, as required for clean separation to daughter cells, while maintaining close parallel alignment of...
A long-standing conundrum is how mitotic chromosomes can compact, as required for clean separation to daughter cells, while maintaining close parallel alignment of sister chromatids. Pursuit of this question, by high resolution 3D fluorescence imaging of living and fixed mammalian cells, has led to three discoveries. First, we show that the structural axes of separated sister chromatids are linked by evenly spaced "mini-axis" bridges. Second, when chromosomes first emerge as discrete units, at prophase, they are organized as co-oriented sister linear loop arrays emanating from a conjoined axis. We show that this same basic organization persists throughout mitosis, without helical coiling. Third, from prophase onward, chromosomes are deformed into sequential arrays of half-helical segments of alternating handedness (perversions), accompanied by correlated kinks. These arrays fluctuate dynamically over <15 s timescales. Together these discoveries redefine the foundation for thinking about the evolution of mitotic chromosomes as they prepare for anaphase segregation.
Topics: Adenosine Triphosphatases; Anaphase; Animals; Cell Cycle Proteins; Chromatids; Chromosomal Proteins, Non-Histone; Chromosomes; DNA Topoisomerases, Type II; DNA-Binding Proteins; Imaging, Three-Dimensional; Mammals; Metaphase; Mitosis; Prophase
PubMed: 32768407
DOI: 10.1016/j.molcel.2020.07.002 -
Current Zoology Apr 2023Despite numerous works devoted to hybrid origin of parthenogenesis in reptiles, the causes of hybridization between different species, resulting in the origin of... (Review)
Review
Despite numerous works devoted to hybrid origin of parthenogenesis in reptiles, the causes of hybridization between different species, resulting in the origin of parthenogenetic forms, remain uncertain. Recent studies demonstrate that sexual species considered parental to parthenogenetic rock lizards ( spp.) avoid interspecific mating in the secondary overlap areas. A specific combination of environmental factors during last glaciation period was critical for ectotherms, which led to a change in their distribution and sex ratio. Biased population structure (e.g., male bias) and limited available distributional range favored the deviation of reproductive behavior when species switched to interspecific mates. To date, at least 7 diploid parthenogenetic species of rock lizards (, Lacertidae) originated through interspecific hybridization in the past. The cytogenetic specifics of meiosis, in particular the weak checkpoints of prophase I, may have allowed the formation of hybrid karyotypes in rock lizards. Hybridization and polyploidization are 2 important evolutionary forces in the genus . At present, throughout backcrossing between parthenogenetic and parental species, the triploid and tetraploid hybrid individuals appear annually, but no triploid species found among spp. on current stage of evolution. The speciation by hybridization with the long-term stage of diploid parthenogenetic species, non-distorted meiosis, together with the high ecological plasticity of Caucasian rock lizards provide us with a new model for considering the pathways and persistence of the evolution of parthenogenesis in vertebrates.
PubMed: 37091994
DOI: 10.1093/cz/zoac036 -
Sexual Development : Genetics,... 2022Germ cells are critical for the survival of our species. They are the only cells that undergo meiosis - the reductive form of cell division that is necessary for genetic... (Review)
Review
BACKGROUND
Germ cells are critical for the survival of our species. They are the only cells that undergo meiosis - the reductive form of cell division that is necessary for genetic reassortment of chromosomes and production of the haploid gametes, the sperm and eggs. Remarkably, the initial female/male fate decision in fetal germ cells does not depend on whether they are chromosomally XX or XY; rather, initial sexual fate is imposed by influences from the surrounding tissue. In mammals, the female germline is particularly precious: despite recent suggestions that germline stem cells exist in the ovary, it is still generally accepted that the ovarian reserve is finite, and its size is dependant on germ cells of the fetal ovary initiating meiosis in a timely manner.
SUMMARY
Prior to 2006, evidence suggested that gonadal germ cells initiate meiotic prophase I by default, but more recent data support a key role for the signalling molecule retinoic acid (RA) in instructing female germ cell fate. Newer findings also support a key meiosis-inducing role for another signalling molecule, bone morphogenic protein (BMP). Nonetheless, many questions remain.
KEY MESSAGES
Here, we review knowledge thus far regarding extrinsic and intrinsic determinants of a female germ cell fate, focusing on the mouse model.
PubMed: 35320803
DOI: 10.1159/000523763 -
Cell Death & Disease Jul 2023Mammalian oocytes spend most of their life in a unique state of cell cycle arrest at meiotic prophase I, during which time they are exposed to countless DNA-damaging...
Mammalian oocytes spend most of their life in a unique state of cell cycle arrest at meiotic prophase I, during which time they are exposed to countless DNA-damaging events. Recent studies have shown that DNA double-strand break repair occurs predominantly via the homologous recombination (HR) pathway in small non-growing meiotically arrested oocytes (primordial follicle stage). However, the DNA repair mechanisms employed by fully grown meiotically arrested oocytes (GV-stage) have not been studied in detail. Here we established a conditional knockout mouse model to explore the role of Ku80, a critical component of the nonhomologous end joining (NHEJ) pathway, in the repair of DNA damage in GV oocytes. GV oocytes lacking Ku80 failed to repair etoposide-induced DNA damage, even when only low levels of damage were sustained. This indicates Ku80 is needed to resolve DSBs and that HR cannot compensate for a compromised NHEJ pathway in fully-grown oocytes. When higher levels of DNA damage were induced, a severe delay in M-phase entry was observed in oocytes lacking XRCC5 compared to wild-type oocytes, suggesting that Ku80-dependent repair of DNA damage is important for the timely release of oocytes from prophase I and resumption of meiosis. Ku80 was also found to be critical for chromosome integrity during meiotic maturation following etoposide exposure. These data demonstrate that Ku80, and NHEJ, are vital for quality control in mammalian GV stage oocytes and reveal that DNA repair pathway choice differs in meiotically arrested oocytes according to growth status.
Topics: Animals; Mice; DNA Damage; DNA End-Joining Repair; DNA Repair; Etoposide; Mammals; Meiosis; Oocytes
PubMed: 37407587
DOI: 10.1038/s41419-023-05886-x -
Frontiers in Plant Science 2022Meiotic crossovers (COs) not only generate genetic diversity but also ensure the accuracy of homologous chromosome segregation. Here, we identified FIGNL1 as a new...
Meiotic crossovers (COs) not only generate genetic diversity but also ensure the accuracy of homologous chromosome segregation. Here, we identified FIGNL1 as a new inhibitor for extra crossover formation in rice. The mutant displays abnormal interactions between non-homologous chromosomes at diakinesis, and chromosome bridges and fragmentation at subsequent stages of meiosis, but shows normal homologous chromosome pairing and synapsis during early prophase I. FIGNL1 participates in homologous chromosome recombination and functions downstream of DMC1. Mutation of increases the number of bivalents in mutants, but does not change the number of HEI10 foci, indicating that FIGNL1 functions in limiting class II CO formation. FIGNL1 interacts with MEICA1, and colocalizes with MEICA1 in a dynamic pattern as punctate foci located between two linear homologous chromosomes. The localization of FIGNL1 depends on ZEP1-mediated assembly of the synaptonemal complex. Based on these results, we propose that FIGNL1 inhibits non-homologous chromosome interaction and CO formation during rice meiosis.
PubMed: 35898226
DOI: 10.3389/fpls.2022.945893 -
Proceedings of the National Academy of... Nov 2022In the early stages of meiosis, maternal and paternal chromosomes pair with their homologous partner and recombine to ensure exchange of genetic information and proper...
In the early stages of meiosis, maternal and paternal chromosomes pair with their homologous partner and recombine to ensure exchange of genetic information and proper segregation. These events can vary drastically between species and between males and females of the same species. In in contrast to females, males do not form synaptonemal complexes (SCs), do not recombine, and have no crossing over; yet, males are able to segregate their chromosomes properly. Here, we investigated the early steps of homolog pairing in males. We found that homolog centromeres are not paired in germline stem cells (GSCs) and become paired in the mitotic region before meiotic entry, similarly to females. Surprisingly, male germline cells express SC proteins, which localize to centromeres and promote pairing. We further found that the SUN/KASH (LINC) complex and microtubules are required for homolog pairing as in females. Chromosome movements in males, however, are much slower than in females and we demonstrate that this slow dynamic is compensated in males by having longer cell cycles. In agreement, slowing down cell cycles was sufficient to rescue pairing-defective mutants in female meiosis. Our results demonstrate that although meiosis differs significantly between males and females, sex-specific cell cycle kinetics integrate similar molecular mechanisms to achieve proper centromere pairing.
Topics: Animals; Male; Female; Chromosome Pairing; Drosophila; Synaptonemal Complex; Centromere; Meiosis; Chromosomes; Chromosome Segregation
PubMed: 36375065
DOI: 10.1073/pnas.2207660119 -
Frontiers in Cell and Developmental... 2022During meiotic prophase I, tightly regulated processes take place, from pairing and synapsis of homologous chromosomes to recombination, which are essential for the...
During meiotic prophase I, tightly regulated processes take place, from pairing and synapsis of homologous chromosomes to recombination, which are essential for the generation of genetically variable haploid gametes. These processes have canonical meiotic features conserved across different phylogenetic groups. However, the dynamics of meiotic prophase I in non-mammalian vertebrates are poorly known. Here, we compare four species from Sauropsida to understand the regulation of meiotic prophase I in reptiles: the Australian central bearded dragon (), two geckos ( and ) and the painted turtle (). We first performed a histological characterization of the spermatogenesis process in both the bearded dragon and the painted turtle. We then analyzed prophase I dynamics, including chromosome pairing, synapsis and the formation of double strand breaks (DSBs). We show that meiosis progression is highly conserved in reptiles with telomeres clustering forming the , which we propose promotes homologous pairing and synapsis, along with facilitating the early pairing of micro-chromosomes during prophase I (i.e., early zygotene). Moreover, we detected low levels of meiotic DSB formation in all taxa. Our results provide new insights into reptile meiosis.
PubMed: 36313577
DOI: 10.3389/fcell.2022.1009776