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The Journal of Biological Chemistry Jun 2024Meiosis reduces ploidy through two rounds of chromosome segregation preceded by one round of DNA replication. In meiosis I, homologous chromosomes segregate, while in...
Meiosis reduces ploidy through two rounds of chromosome segregation preceded by one round of DNA replication. In meiosis I, homologous chromosomes segregate, while in meiosis II, sister chromatids separate from each other. Topoisomerase II (Topo II) is a conserved enzyme that alters DNA structure by introducing transient double-strand breaks. During mitosis, Topo II relieves topological stress associated with unwinding DNA during replication, recombination, and sister chromatid segregation. Topo II also plays a role in maintaining mitotic chromosome structure. However, the role and regulation of Topo II during meiosis is not well-defined. Previously, we found an allele of Topo II, top-2(it7), disrupts homologous chromosome segregation during meiosis I of Caenorhabditis elegans spermatogenesis. In a genetic screen, we identified different point mutations in 5'-tyrosyl-DNA phosphodiesterase two (Tdp2, C. elegans tdpt-1) that suppress top-2(it7) embryonic lethality. Tdp2 removes trapped Top-2-DNA complexes. The tdpt-1 suppressing mutations rescue embryonic lethality, ameliorate chromosome segregation defects, and restore TOP-2 protein levels of top-2(it7). Here, we show that both TOP-2 and TDPT-1 are expressed in germ line nuclei but occupy different compartments until late meiotic prophase. We also demonstrate that tdpt-1 suppression is due to loss of function of the protein and that the tdpt-1 mutations do not have a phenotype independent of top-2(it7) in meiosis. Lastly, we found that the tdpt-1 suppressing mutations either impair the phosphodiesterase activity, affect the stability of TDPT-1, or disrupt protein interactions. This suggests that the WT TDPT-1 protein is inhibiting chromosome biological functions of an impaired TOP-2 during meiosis.
PubMed: 38844130
DOI: 10.1016/j.jbc.2024.107446 -
Cell Structure and Function Jun 2024In metazoans, the nuclear envelope (NE) disassembles during the prophase and reassembles around segregated chromatids during the telophase. The process of NE formation...
In metazoans, the nuclear envelope (NE) disassembles during the prophase and reassembles around segregated chromatids during the telophase. The process of NE formation has been extensively studied using live-cell imaging. At the early step of NE reassembly in human cells, specific pattern-like localization of inner nuclear membrane (INM) proteins, connected to the nuclear pore complex (NPC), was observed in the so-called "core" region and "noncore" region on telophase chromosomes, which corresponded to the "pore-free" region and the "pore-rich" region, respectively, in the early G1 interphase nucleus. We refer to these phenomena as NE subdomain formation. To biochemically investigate this process, we aimed to develop an in vitro NE reconstitution system using digitonin-permeabilized semi-intact mitotic human cells coexpressing two INM proteins, emerin and lamin B receptor, which were labeled with fluorescent proteins. The targeting and accumulation of INM proteins to chromosomes before and after anaphase onset in semi-intact cells were observed using time-lapse imaging. Our in vitro NE reconstitution system recapitulated the formation of the NE subdomain, as in living cells, although chromosome segregation and cytokinesis were not observed. This in vitro NE reconstitution required the addition of a mitotic cytosolic fraction supplemented with a cyclin-dependent kinase inhibitor and energy sources. The cytoplasmic soluble factor(s) dependency of INM protein targeting differed among the segregation states of chromosomes. Furthermore, the NE reconstituted on segregated chromosomes exhibited active nucleocytoplasmic transport competency. These results indicate that the chromosome status changes after anaphase onset for recruiting NPC components.Key words: nuclear envelope reassembly, inner nuclear membrane protein, nuclear pore complex, semi-intact cell, in vitro reconstitution.
PubMed: 38839376
DOI: 10.1247/csf.24003 -
Zygote (Cambridge, England) Jun 2024The intra-ovarian presence of ootids, i.e. female gametes that have completed meiosis, is considered exceptional in the animal kingdom. The present study explores the...
The intra-ovarian presence of ootids, i.e. female gametes that have completed meiosis, is considered exceptional in the animal kingdom. The present study explores the first such case to be reported in a sea cucumber (Echinodermata: Holothuroidea). In the overwhelming majority of animals, including holothuroids, oocytes (i.e. immature female gametes) that are developing in the ovary undergo a primary arrest at the prophase stage of meiosis, which may last from days to decades. In free-spawning taxa, this arrest is normally lifted only during or shortly before transit in the gonoduct, when gamete release (spawning) is imminent. However, oocytes of the holothuroid were discovered to have resumed the second meiotic division including the completion of germinal vesicle breakdown and polar-body expulsion inside the ovary, effectively reaching the ootid stage concomitantly with ovulation (i.e. escape from follicle cells) prior to spawning. The potential drivers and significance of this exceptionally rare case of full intra-ovarian oogenic maturation are discussed.
PubMed: 38828553
DOI: 10.1017/S0967199424000170 -
Biological Research May 2024Helicase for meiosis 1 (HFM1), a putative DNA helicase expressed in germ-line cells, has been reported to be closely associated with premature ovarian insufficiency...
BACKGROUND
Helicase for meiosis 1 (HFM1), a putative DNA helicase expressed in germ-line cells, has been reported to be closely associated with premature ovarian insufficiency (POI). However, the underlying molecular mechanism has not been clearly elucidated. The aim of this study was to investigate the function of HFM1 in the first meiotic prophase of mouse oocytes.
RESULTS
The results suggested that the deficiency of HFM1 resulting in increased apoptosis and depletion of oocytes in mice, while the oocytes were arrested in the pachytene stage of the first meiotic prophase. In addition, impaired DNA double-strand break repair and disrupted synapsis were observed in the absence of HFM1. Further investigation revealed that knockout of HFM1 promoted ubiquitination and degradation of FUS protein mediated by FBXW11. Additionally, the depletion of HFM1 altered the intranuclear localization of FUS and regulated meiotic- and oocyte development-related genes in oocytes by modulating the expression of BRCA1.
CONCLUSIONS
These findings elaborated that the critical role of HFM1 in orchestrating the regulation of DNA double-strand break repair and synapsis to ensure meiosis procession and primordial follicle formation. This study provided insights into the pathogenesis of POI and highlighted the importance of HFM1 in maintaining proper meiotic function in mouse oocytes.
Topics: Animals; Female; Mice; Apoptosis; DNA Breaks, Double-Stranded; DNA Repair; Meiosis; Meiotic Prophase I; Mice, Knockout; Oocytes; RNA-Binding Protein FUS; Ubiquitination
PubMed: 38822414
DOI: 10.1186/s40659-024-00518-w -
Integrative Zoology May 2024Plateau zokor (Eospalax baileyi) is a subterranean rodent and seasonal breeder. During the non-breeding season, the testicles regress, leading to the arrest of...
Plateau zokor (Eospalax baileyi) is a subterranean rodent and seasonal breeder. During the non-breeding season, the testicles regress, leading to the arrest of spermatogenesis and loss of fertility. The identification of the specific germ cell type at which spermatogenesis is arrested, as well as potential regulatory factors during the non-breeding season, is important for understanding seasonal spermatogenesis in subterranean species. This study analyzed genes in spermatocytes of plateau zokor by referring to single-cell RNA results in mice. We discovered that spermatogenesis is arrested at the spermatocyte during the non-breeding season, which was corroborated via immunofluorescence staining results. The analysis of gene expression during different stages of meiotic prophase I has revealed that germ cell development may be arrested, starting from zygonema, during the non-breeding season. Meanwhile, we discovered that the apoptosis genes were up-regulated, leading to apoptosis in spermatocytes. To confirm that the germ cell differentiation was blocked during the non-breeding season due to a decrease in the androgen level, we used androgen receptor antagonist (flutamide) to intervene in the breeding season and found that the inner diameter of the seminiferous tubules was significantly reduced, spermatogenesis was arrested, and spermatocytes underwent apoptosis. This study revealed that spermatocytes are the terminal of germ cell differentiation in plateau zokor during the non-breeding season and that the arrest of differentiation is attributed to a decline in androgen levels. Our results complement the theoretical basis of seasonal reproduction in plateau zokor.
PubMed: 38816925
DOI: 10.1111/1749-4877.12849 -
Neuropsychiatric Disease and Treatment 2024Schizophrenia is a severe mental illness that usually begins in late adolescence or early adulthood. Current pharmacological treatments, while acceptably effective for...
INTRODUCTION
Schizophrenia is a severe mental illness that usually begins in late adolescence or early adulthood. Current pharmacological treatments, while acceptably effective for many patients, are rarely clinically tailored or individualized. The lack of sufficient etiopathological knowledge of the disease, together with overall comparable effect sizes for efficacy between available antipsychotics and the absence of clinically actionable biomarkers, has hindered the advance of individualized medicine in the treatment of schizophrenia. Nevertheless, some degree of stratification based on clinical markers could guide treatment choices and help clinicians move toward individualized psychiatry. To this end, a panel of experts met to formally discuss the current approach to individualized treatment in schizophrenia and to define how treatment individualization could help improve clinical outcomes.
METHODS
A task force of seven experts iteratively developed, evaluated, and refined questionnaire items, which were then evaluated using the Delphi method. Descriptive statistics were used to summarize and rank expert responses. Expert discussion, informed by the results of a scoping review on personalizing the pharmacologic treatment of adults and adolescents with schizophrenia, ultimately generated recommendations to guide individualized pharmacologic treatment in this population.
RESULTS
There was substantial agreement among the expert group members, resulting in the following recommendations: 1) individualization of treatment requires consideration of the patient's diagnosis, clinical presentation, comorbidities, previous treatment response, drug tolerability, adherence patterns, and social factors; 2) patient preferences should be considered in a shared decision-making approach; 3) identified barriers to personalized care that need to be overcome include the lack of actionable biomarkers and mechanistic similarities between available treatments, but digital tools should be increasingly used to enhance individualized treatment.
CONCLUSION
Individualized care can help provide effective, tailored treatments based on an individual's clinical characteristics, disease trajectory, family and social environment, and goals and preferences.
PubMed: 38812809
DOI: 10.2147/NDT.S456163 -
Zoological Science Jun 2024Formation of the synaptonemal complex (SC) is a prerequisite for proper recombination and chromosomal segregation during meiotic prophase I. One mechanism that ensures...
Formation of the synaptonemal complex (SC) is a prerequisite for proper recombination and chromosomal segregation during meiotic prophase I. One mechanism that ensures SC formation is chromosomal movement, which is driven by the force derived from cytoskeletal motors. Here, we report the phenotype of medaka mutants lacking the telomere repeat binding bouquet formation protein 1 (TERB1), which, in combination with the SUN/KASH protein, mediates chromosomal movement by connecting telomeres and cytoskeletal motors. Mutations in the gene exhibit defects in SC formation in medaka. Although SC formation was initiated, as seen by the punctate lateral elements and fragmented transverse filaments, it was not completed in the mutant meiocytes. The mutant phenotype further revealed that the introduction of double strand breaks was independent of synapsis completion. In association with these phenotypes, meiocytes in both the ovaries and testes exhibited an aberrant arrangement of homologous chromosomes. Interestingly, although oogenesis halted at the zygotene-like stage in mutant, testes continued to produce sperm-like cells with aberrant DNA content. This indicates that the mechanism of meiotic checkpoint is sexually different in medaka, similar to the mammalian checkpoint in which oogenesis proceeds while spermatogenesis is arrested. Moreover, our results suggest that spermatogenesis is mechanistically dissociable from meiosis.
Topics: Animals; Oryzias; Synaptonemal Complex; Male; Gametogenesis; Female; Mutation; Meiosis; Fish Proteins
PubMed: 38809870
DOI: 10.2108/zs230108 -
Molecular Aspects of Medicine Jun 2024Meiosis is a critical step for spermatogenesis and oogenesis. Meiosis commences with pre-meiotic S phase that is subsequently followed by meiotic prophase. The meiotic... (Review)
Review
Meiosis is a critical step for spermatogenesis and oogenesis. Meiosis commences with pre-meiotic S phase that is subsequently followed by meiotic prophase. The meiotic prophase is characterized by the meiosis-specific chromosomal events such as chromosome recombination and homolog synapsis. Meiosis initiator (MEIOSIN) and stimulated by retinoic acid gene 8 (STRA8) initiate meiosis by activating the meiotic genes by installing the meiotic prophase program at pre-meiotic S phase. This review highlights the mechanisms of meiotic initiation and meiotic prophase progression from the point of the gene expression program and its relevance to infertility. Furthermore, upstream pathways that regulate meiotic initiation will be discussed in the context of spermatogenic development, indicating the sexual differences in the mode of meiotic entry.
Topics: Spermatogenesis; Humans; Meiosis; Animals; Male; Meiotic Prophase I; Prophase
PubMed: 38797021
DOI: 10.1016/j.mam.2024.101282 -
Mathematical Biosciences May 2024This paper develops a theory for anaphase in cells. After a brief description of microtubules, the mitotic spindle and the centrosome, a mathematical model for anaphase...
This paper develops a theory for anaphase in cells. After a brief description of microtubules, the mitotic spindle and the centrosome, a mathematical model for anaphase is introduced and developed in the context of the cell cytoplasm and liquid crystalline structures. Prophase, prometaphase and metaphase are then briefly described in order to focus on anaphase, which is the main study of this paper. The entities involved are modelled in terms of liquid crystal defects and microtubules are represented as defect flux lines. The mathematical techniques employed make extensive use of energy considerations based on the work that was developed by Dafermos (1970) from the classical Frank-Oseen nematic liquid crystal energy (Frank, 1958; Oseen, 1933). With regard to liquid crystal theory we introduce the concept of regions of influence for defects which it is believed have important implications beyond the subject of this paper. The results of this paper align with observed biochemical phenomena and are explored in application to HeLa cells and Caenorhabditis elegans. This unified approach offers the possibility of gaining insight into various consequences of mitotic abnormalities which may result in Down syndrome, Hodgkin lymphoma, breast, prostate and various other types of cancer.
PubMed: 38795952
DOI: 10.1016/j.mbs.2024.109219 -
Chemosphere Jul 2024The resuspension of phosphorus (P) in sediments has the most significant contribution to the overlying water. The PP release characterization during resuspension was...
The resuspension of phosphorus (P) in sediments has the most significant contribution to the overlying water. The PP release characterization during resuspension was investigated. The results indicated that the P in suspensions had more release risk compared to the sediments. The particulate P (PP) concentration (0.54 mg L) under high-intensity rotational speed (250 rad min) was about five times higher than others (0.11 mg L). The sorption parameters of zero equilibrium P concentration (EPC) and soluble reactive P (SRP) were significantly correlated with each other (p < 0.01, r = 0.73). Suspended solids expressed stronger P source than sediments. The values of EPC was highly significantly correlated with the sorption coefficient (K) and native adsorbed P (NAP) (p < 0.01). The mean values of NAP were 0.0612 mg g and 0.0604 mg g in the Prophase and Metaphase, respectively, and 0.0586 mg g at Anaphase. The values of P sorption index (PSI) ranged from 0.4359 to 0.6862 L g, with mean values of 0.5350 L g (Prophase), 0.6061 L g (Metaphase), and 0.4967 L g (Anaphase). The degree of P saturation (DPS) decreased in the order of Anaphase (2.73%) > Prophase (2.53%) > Metaphase (2.12%). The release risk index of P (ERI) decreased in the order of Anaphase (5.47%) > Prophase (4.72%) > Metaphase (3.59%), with a range of 2.12%-8.56%. To fast and slow scale, the results of NaOH-P (V<0, V>0) contribution indicated that the persistent disturbance promoted the release of adsorbed dissolved PP from NaOH-P in suspended sediment to the overlying water. The contribution of HCl-P (V > 0) was positive in the Anaphase of the slow scale, and HCl-P was a PP source in the frequently disturbing conditions.
Topics: Phosphorus; Geologic Sediments; Water Pollutants, Chemical; Environmental Monitoring; Adsorption
PubMed: 38777196
DOI: 10.1016/j.chemosphere.2024.142386