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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 -
Antioxidants & Redox Signaling Feb 2024Acetaminophen (APAP) is clinically recommended as analgesic and antipyretic among pregnant women. However, accumulating laboratory evidence shows that the use of APAP...
Acetaminophen (APAP) is clinically recommended as analgesic and antipyretic among pregnant women. However, accumulating laboratory evidence shows that the use of APAP during pregnancy may alter fetal development. Since fetal stage is a susceptible window for early oogenesis, we aim to assess the potential effects of maternal administration of APAP on fetal oocytes. Pregnant mice at 14.5 dpc (days post-coitus) were orally administered with APAP (50 and 150mg/kg.bw/day) for 3 days; meanwhile, 14.5 dpc ovaries were collected and cultured with APAP or its metabolite N-acetyl-p-benzoquinone imine (NAPQI; 5 and 15 μ) for 3 days. It showed that APAP caused meiotic aberrations in fetal oocytes through its metabolite NAPQI, including meiotic prophase I (MPI) progression delay and homologous recombination defects. Co-treatment with nicotinamide (NAM) or nicotinamide riboside chloride (NRC), nicotinamide adenine dinucleotide (NAD) supplements, efficiently restored the MPI arrest, whereas the addition of the inhibitor of sirtuin 7 (SIRT7) invalidated the effect of the NAD supplement. In addition, RNA sequencing revealed distorted transcriptomes of fetal ovaries treated with NAPQI. Furthermore, the fecundity of female offspring was affected, exhibiting delayed primordial folliculogenesis and puberty onset, reduced levels of ovarian hormones, and impaired developmental competence of MII oocytes. These findings provide the first known demonstration that NAPQI, converted from maternal administration of APAP, disturbs meiotic process of fetal oocytes and further impairs female fecundity in adulthood. The concomitant oral dosing with NAM further supports the benefits of NAD supplements on oogenesis. Short-term administration of APAP to pregnant mouse caused meiotic aberrations in fetal oocytes by its metabolite NAPQI, whereas co-treatment with NAD supplement efficiently relieves the adverse effects by interacting with SIRT7.
PubMed: 38062739
DOI: 10.1089/ars.2023.0270 -
Human Reproduction (Oxford, England) Nov 2023Are variants of genes involved in meiosis initiation responsible for premature ovarian insufficiency (POI)?
STUDY QUESTION
Are variants of genes involved in meiosis initiation responsible for premature ovarian insufficiency (POI)?
SUMMARY ANSWER
A MEIOSIN variant participates in the pathogenesis of human POI by impairing meiosis due to insufficient transcriptional activation of essential meiotic genes.
WHAT IS KNOWN ALREADY
Meiosis is the key event for the establishment of the ovarian reserve, and several gene defects impairing meiotic homologous recombination have been found to contribute to the pathogenesis of POI. Although STRA8 and MEIOISN variants have been found to associate with POI in a recent study, the condition of other meiosis initiation genes is unknown and direct evidence of variants participating in the pathogenesis of POI is still lacking.
STUDY DESIGN, SIZE, DURATION
This was a retrospective genetic study. An in-house whole exome sequencing (WES) database of 1030 idiopathic POI patients was screened for variations of meiosis initiation genes.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Homozygous or compound heterozygous variations of genes involved in meiosis initiation were screened in the in-house WES database. The pathogenicity of the variation was verified by in vitro experiments, including protein structure prediction and dual-luciferase reporter assay. The effect of the variant on ovarian function and meiosis was demonstrated through histological analyses in a point mutation mouse model.
MAIN RESULTS AND THE ROLE OF CHANCE
One homozygous variant in MEIOSIN (c.1735C>T, p.R579W) and one in STRA8 (c.258 + 1G>A), which initiates meiosis via the retinoic acid-dependent pathway, were identified in a patient with idiopathic POI respectively. The STRA8 variation has been reported in the recently published work. For the MEIOSIN variation, the dual-luciferase reporter assay revealed that the variant adversely affected the transcriptional function of MEIOSIN in upregulating meiotic genes. Furthermore, knock-in mice with the homologous mutation confirmed that the variation impacted the meiotic prophase I program and accelerated oocyte depletion. Moreover, the variant p.R579W localizing in the high-mobility group (HMG) box domain disrupted the nuclear localization of the MEIOSIN protein but was dispensable for the cell-cycle switch of oocytes, suggesting a unique role of the MEIOSIN HMG box domain in meiosis initiation.
LIMITATIONS, REASONS FOR CAUTION
Further studies are needed to explore the role of other meiosis initiation genes in the pathogenesis of POI.
WIDER IMPLICATIONS OF THE FINDINGS
The MEIOSIN variant was verified to cause POI by impaired transcriptional regulation of meiotic genes and was inherited by a recessive mode. The function of HMG box domain in MEIOSIN protein was also expanded by this study. Although causative variations in meiotic initiation genes are rare in POI, our study confirmed the pathogenicity of a MEIOSIN variant and elucidated another mechanism of human infertility.
STUDY FUNDING/COMPETING INTEREST(S)
This work was supported by the National Key Research & Developmental Program of China (2022YFC2703800, 2022YFC2703000), National Natural Science Foundation for Distinguished Young Scholars (82125014), National Natural Science Foundation of China (32070847, 32170867, 82071609), Basic Science Center Program of NSFC (31988101), Natural Science Foundation of Shandong Province for Grand Basic Projects (ZR2021ZD33), Natural Science Foundation of Shandong Province for Excellent Young Scholars (ZR2022YQ69), Taishan Scholars Program for Young Experts of Shandong Province (tsqn202211371), and Qilu Young Scholars Program of Shandong University. The authors declare no conflict of interest.
TRIAL REGISTRATION NUMBER
N/A.
Topics: Humans; Animals; Mice; Female; Meiosis; Retrospective Studies; Menopause, Premature; Primary Ovarian Insufficiency; Luciferases
PubMed: 37982418
DOI: 10.1093/humrep/dead084 -
Ecotoxicology and Environmental Safety Dec 2023Accumulation of the heavy metal Cadmium (Cd) in the ovaries and placenta can affect the structure and function of these organs and induce female reproductive toxicity....
Accumulation of the heavy metal Cadmium (Cd) in the ovaries and placenta can affect the structure and function of these organs and induce female reproductive toxicity. This toxicity may be due to Cd's similarity to estrogen and its ability to disrupt endocrine systems. However, the exact molecular mechanism by which Cd causes reproductive toxicity at the transcriptome level remains poorly understood. Hence, this study aimed to observe Cd-induced reproductive damage at the gene level, scrutinize the repercussions of Cd exposure on oogenesis, and explicate the putative pathogenesis of Cd-induced oogenesis based on Caenorhabditis elegans (C. elegans) as an in vivo model. The results showed that Cd exposure significantly decreased the number of offspring and prolonged the reproductive span of C. elegans. Cd exposure also reduced the number of cells in mitosis and the pachytene and diakinesis stages of meiosis, thereby disrupting oogenesis. Combined with transcriptional sequencing and bioinformatics analysis, a total of 3167 DEmRNAs were identified. Regarding gene expression, cul-6, mum-2, and vang-1 were found to be related to Cd-induced reproductive toxicity, and their competing endogenous RNA networks were constructed. We observed that mutations of mom-2 and vang-1 in the Wnt pathway could induce susceptibility to Cd-caused meiosis injury. In conclusion, the results indicated that Cd could impair the oogenesis of C. elegans and the Wnt pathway might serve as a protective mechanism against Cd reproductive toxicity. These findings contribute to a better understanding of the damaging effects and molecular biological mechanisms of Cd on the human reproductive system.
Topics: Animals; Female; Humans; Caenorhabditis elegans; Cadmium; RNA; Oogenesis; Metals, Heavy; Caenorhabditis elegans Proteins
PubMed: 37976926
DOI: 10.1016/j.ecoenv.2023.115687 -
Genes To Cells : Devoted To Molecular &... Jan 2024The mitotic cohesin complex necessary for sister chromatid cohesion and chromatin loop formation shows local and global association to chromosomes in response to DNA...
The mitotic cohesin complex necessary for sister chromatid cohesion and chromatin loop formation shows local and global association to chromosomes in response to DNA double-strand breaks (DSBs). Here, by genome-wide binding analysis of the meiotic cohesin with Rec8, we found that the Rec8-localization profile along chromosomes is altered from middle to late meiotic prophase I with cleavage-independent dissociation. Each Rec8-binding site on the chromosome axis follows a unique alternation pattern with dissociation and probably association. Centromeres showed altered Rec8 binding in late prophase I relative to mid-prophase I, implying chromosome remodeling of the regions. Rec8 dissociation ratio per chromosome is correlated well with meiotic DSB density. Indeed, the spo11 mutant deficient in meiotic DSB formation did not change the distribution of Rec8 along chromosomes in late meiotic prophase I. These suggest the presence of a meiosis-specific regulatory pathway for the global binding of Rec8-cohesin in response to DSBs.
Topics: Cell Cycle Proteins; Cohesins; DNA; DNA Breaks, Double-Stranded; Meiosis; Saccharomyces cerevisiae
PubMed: 37968127
DOI: 10.1111/gtc.13081 -
Developmental Cell Dec 2023During meiosis, the chromatin and transcriptome undergo prominent switches. Although recent studies have explored the genome reorganization during spermatogenesis, the...
During meiosis, the chromatin and transcriptome undergo prominent switches. Although recent studies have explored the genome reorganization during spermatogenesis, the chromatin remodeling in oogenesis and characteristics of homologous pairing remain largely elusive. We comprehensively compared chromatin structures and transcriptomes at successive substages of meiotic prophase in both female and male mice using low-input high-through chromosome conformation capture (Hi-C) and RNA sequencing (RNA-seq). Compartments and topologically associating domains (TADs) gradually disappeared and slowly recovered in both sexes. We found that homologs adopted different sex-conserved pairing strategies prior to and after the leptotene-to-zygotene transition, changing from long interspersed nuclear element (LINE)-enriched compartments B to short interspersed nuclear element (SINE)-enriched compartments A. We complemented marker genes and predicted the sex-specific meiotic sterile genes for each substage. This study provides valuable insights into the similarities and distinctions between sexes in chromosome architecture, homologous pairing, and transcriptome during meiotic prophase of both oogenesis and spermatogenesis.
Topics: Male; Female; Mice; Animals; Meiosis; Spermatogenesis; Prophase; Meiotic Prophase I; Chromatin; Oogenesis; Chromosome Pairing
PubMed: 37963468
DOI: 10.1016/j.devcel.2023.10.009 -
PLoS Genetics Nov 2023The meiotic recombination checkpoint reinforces the order of events during meiotic prophase I, ensuring the accurate distribution of chromosomes to the gametes. The AAA+...
The meiotic recombination checkpoint reinforces the order of events during meiotic prophase I, ensuring the accurate distribution of chromosomes to the gametes. The AAA+ ATPase Pch2 remodels the Hop1 axial protein enabling adequate levels of Hop1-T318 phosphorylation to support the ensuing checkpoint response. While these events are localized at chromosome axes, the checkpoint activating function of Pch2 relies on its cytoplasmic population. In contrast, forced nuclear accumulation of Pch2 leads to checkpoint inactivation. Here, we reveal the mechanism by which Pch2 travels from the cell nucleus to the cytoplasm to maintain Pch2 cellular homeostasis. Leptomycin B treatment provokes the nuclear accumulation of Pch2, indicating that its nucleocytoplasmic transport is mediated by the Crm1 exportin recognizing proteins containing Nuclear Export Signals (NESs). Consistently, leptomycin B leads to checkpoint inactivation and impaired Hop1 axial localization. Pch2 nucleocytoplasmic traffic is independent of its association with Zip1 and Orc1. We also identify a functional NES in the non-catalytic N-terminal domain of Pch2 that is required for its nucleocytoplasmic trafficking and proper checkpoint activity. In sum, we unveil another layer of control of Pch2 function during meiosis involving nuclear export via the exportin pathway that is crucial to maintain the critical balance of Pch2 distribution among different cellular compartments.
Topics: Saccharomyces cerevisiae Proteins; Meiosis; Saccharomyces cerevisiae; Active Transport, Cell Nucleus; Nuclear Proteins; DNA-Binding Proteins; Karyopherins; Homeostasis
PubMed: 37948444
DOI: 10.1371/journal.pgen.1011026 -
Frontiers in Plant Science 2023Transposable elements (TEs) and satellite DNAs, two major categories of repetitive sequences, are expected to accumulate in non-recombining genome regions, including...
Transposable elements (TEs) and satellite DNAs, two major categories of repetitive sequences, are expected to accumulate in non-recombining genome regions, including sex-linked regions, and contribute to sex chromosome evolution. The dioecious plant, , can be used for studying the evolution of the XX/XYY sex chromosomes. In this study, we thoroughly examined the repetitive components of male and female using next-generation sequencing data followed by bioinformatics analysis and florescence hybridization (FISH). The genome has a high overall repetitive sequence composition, 68.30% in the female and 66.78% in the male genome, with abundant long terminal repeat (LTR) retrotransposons (RTs), including more Ty3/ than Ty1/ elements, particularly two Ty3/ lineages, Tekay and Retand. Most LTR-RT lineages were found dispersed across the chromosomes, though CRM and Athila elements were predominately found within the centromeres and the pericentromeric regions. The Athila elements also showed clearly higher FISH signal intensities in the Y and Y chromosomes than in the X or autosomes. Three novel satellite DNAs were specifically distributed in the centromeric and/or telomeric regions, with markedly different distributions on the X, Y, and Y chromosomes. Combined with FISH using satellite DNAs to stain chromosomes during meiotic diakinesis, we determined the synapsis pattern and distinguish pseudoautosomal regions (PARs). The results indicate that the XYY sex chromosomes of might have originated from a centric fission event. This study improves our understanding of the repetitive sequence organization of genome and provides a basis for further analysis of their chromosome evolution process.
PubMed: 37908838
DOI: 10.3389/fpls.2023.1230250 -
Biomedicines Sep 2023Diabetes mellitus is a metabolic disease that can cause systemic problems, including testicular dysfunction. Several diabetes medications have demonstrated potential...
Diabetes mellitus is a metabolic disease that can cause systemic problems, including testicular dysfunction. Several diabetes medications have demonstrated potential adverse effects on the male reproductive system; however, the effects of saxagliptin and dapagliflozin have not been sufficiently examined. This investigation studied the impacts of saxagliptin and dapagliflozin treatments on the gonads in a male mouse model of diabetes. Testicular disturbances were assessed by sperm DNA damage, diakinesis-metaphase I chromosome examination, and spermiogram analysis. Our results showed more sperm DNA damage, more spermatocyte chromosome aberrations, lower sperm motility/count, and more sperm morphological anomalies in diabetic mice than in the control mice. Dapagliflozin significantly restored all examined measures to the control values in diabetic mice, unlike saxagliptin, which exacerbated the reduction in sperm count and motility. Both drugs significantly restored the gonadal redox imbalances in diabetic mice by decreasing reactive oxygen species accumulation and increasing glutathione levels. In conclusion, our study presents preliminary evidence for the safety and efficacy of dapagliflozin in alleviating testicular abnormalities induced by diabetes, making it a promising candidate drug for patients with diabetes in their reproductive age. As saxagliptin may have negative effects on fertility, its prescription should be avoided in young male diabetic patients.
PubMed: 37893048
DOI: 10.3390/biomedicines11102674 -
Nature Communications Oct 2023The formation of RAD51/DMC1 filaments on single-stranded (ss)DNAs essential for homology search and strand exchange in DNA double-strand break (DSB) repair is tightly...
The formation of RAD51/DMC1 filaments on single-stranded (ss)DNAs essential for homology search and strand exchange in DNA double-strand break (DSB) repair is tightly regulated. FIGNL1 AAA+++ ATPase controls RAD51-mediated recombination in human cells. However, its role in gametogenesis remains unsolved. Here, we characterized a germ line-specific conditional knockout (cKO) mouse of FIGNL1. Fignl1 cKO male mice showed defective chromosome synapsis and impaired meiotic DSB repair with the accumulation of RAD51/DMC1 on meiotic chromosomes, supporting a positive role of FIGNL1 in homologous recombination at a post-assembly stage of RAD51/DMC1 filaments. Fignl1 cKO spermatocytes also accumulate RAD51/DMC1 on chromosomes in pre-meiotic S-phase. These RAD51/DMC1 assemblies are independent of meiotic DSB formation. We also showed that purified FIGNL1 dismantles RAD51 filament on double-stranded (ds)DNA as well as ssDNA. These results suggest an additional role of FIGNL1 in limiting the non-productive assembly of RAD51/DMC1 on native dsDNAs during pre-meiotic S-phase and meiotic prophase I.
Topics: Male; Humans; Animals; Mice; Meiosis; Rad51 Recombinase; DNA-Binding Proteins; ATPases Associated with Diverse Cellular Activities; DNA Breaks, Double-Stranded; Cell Cycle Proteins; Homologous Recombination; DNA; DNA Replication; Microtubule-Associated Proteins; Nuclear Proteins
PubMed: 37891173
DOI: 10.1038/s41467-023-42576-w