Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.920
Filtrar
1.
Exp Suppl ; 111: 341-366, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588539

RESUMO

Male infertility is a multifactorial and heterogeneous pathological condition affecting 7% of the general male population. The genetic landscape of male infertility is highly complex as semen and testis histological phenotypes are extremely heterogeneous, and at least 2000 genes are predicted to be involved in spermatogenesis. Genetic factors have been described in each etiological category of male reproductive impairment: (1) hypothalamic-pituitary axis dysfunction; (2) quantitative and qualitative alterations of spermatogenesis; (3) ductal obstruction/dysfunction. In 25% of azoospermic and in 10% of oligozoospermic men, a genetic anomaly can be diagnosed with the current genetic testing. However, up to now, only a relatively low number of monogenic factors have a clear-cut cause-effect relationship with impaired reproductive function. Thanks to the widespread diffusion of Next-Generation Sequencing, a continuously increasing number of monogenic causes of male infertility are being discovered and their validation is currently ongoing. The identification of genetic factors is of outmost clinical importance since there is a risk of transmission of genetic defects through natural or assisted reproductive techniques. The benefit of the genetic diagnosis of infertility has an obvious clinical significance for the patient itself with implications not only for his reproductive health but in many instances also for his general health.


Assuntos
Infertilidade Masculina/genética , Espermatogênese/genética , Testes Genéticos , Humanos , Masculino
2.
Toxicol Lett ; 315: 31-38, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31419471

RESUMO

Endocrine disruptor zearalenone (ZEA) has been found to damage the reproductive system especially spermatogenesis. In our previous report, we have found that low dose (lower than No-Observed Effect Level, NOEL) ZEA exposure disturbed mouse spermatogenesis and diminished mouse semen quality. The purpose of current investigation was to explore the underlying mechanisms of pubertal low dose ZEA exposure upsetting spermatogenesis. And it was demonstrated that pubertal low dose ZEA exposure disrupted the meiosis process and the important genetic pathways to inhibit the spermatogenesis and even to diminish the semen quality with the decrease in spermatozoa motility and concentration. The DNA methylation markers 5mC and 5hmC were decreased, the histone methylation marker H3K27 was increased, at the same time estrogen receptor alpha was diminished in mouse testis after pubertal low dose ZEA exposure. The data indicate that the disruption in spermatogenesis by pubertal low dose ZEA exposure may be through the alterations in genetic and epigenetic pathways, and the interactions with estrogen receptor signaling pathway. Therefore, we should pay great attention on ZEA exposure to reduce its adverse impacts on male reproductive health.


Assuntos
Divisão Celular/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Receptor alfa de Estrogênio/efeitos dos fármacos , Motilidade Espermática/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Espermatogênese/genética , Zearalenona/toxicidade , Adolescente , Animais , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Transdução de Sinais/efeitos dos fármacos
3.
Gene ; 719: 144074, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31446094

RESUMO

Kinesin-14 motor es-kifc1 is highly expressed in the male reproductive system of the Chinese mitten crab Eriocheir sinensis (E. sinensis). In addition to acrosomal formation, es-KIFC1 also tightly surrounds the nucleus and its specific mechanism remains unknown. During spermatogenesis, sperm nucleus dents into a cup-shaped structure with several radial arms and completed the nuclear decondensation. In this study, the spatial expression pattern of es-KIFC1 indicates a potential function in nuclear formation with the nuclear localization sequence (NLS) on N-terminal domain which is crucial for the translocation of es-KIFC1 into the nucleus. The Motor domain is associated with microtubule modulation and the Golgi vesicles positioning. Furthermore, the expression level of es-KIFC1 is not only related to the seasonal variation of crustacean development, but also associates with mature sperm storage. The double strand RNA (dsRNA) mediated RNA interference manifests that the cup-shaped sperm nucleus is remarkably malformed and even separates the chromatin throughout the nuclei at the last stage of spermiogenesis. Besides, the sperm nucleus almost disperses its structure and separates the chromatin into several segments throughout the nucleus showing an asymmetrical performance without cytoskeleton. In summary, these results indicate the importance of es-KIFC1 in microtubule positioning and the maintenance of the mature sperm nuclei.


Assuntos
Proteínas de Artrópodes/genética , Braquiúros/fisiologia , Núcleo Celular/metabolismo , Cinesina/genética , Espermatogênese/genética , Animais , Proteínas de Artrópodes/metabolismo , Núcleo Celular/ultraestrutura , Citoesqueleto/metabolismo , Cinesina/metabolismo , Masculino , Microtúbulos/metabolismo , Transporte Proteico , RNA de Cadeia Dupla/genética , Espermatozoides/ultraestrutura
4.
BMC Evol Biol ; 19(1): 137, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31269894

RESUMO

BACKGROUND: Previously, we have demonstrated that genes involved in ovarian function are highly conserved throughout evolution. In this study, we aimed to document the conservation of genes involved in spermatogenesis from flies to vertebrates and their expression profiles in vertebrates. RESULTS: We retrieved 379 Drosophila melanogaster genes that are functionally involved in male reproduction according to their mutant phenotypes and listed their vertebrate orthologs. 83% of the fly genes have at least one vertebrate ortholog for a total of 625 mouse orthologs. This conservation percentage is almost twice as high as the 42% rate for the whole fly genome and is similar to that previously found for genes preferentially expressed in ovaries. Of the 625 mouse orthologs, we selected 68 mouse genes of interest, 42 of which exhibited a predominant relative expression in testes and 26 were their paralogs. These 68 mouse genes exhibited 144 and 60 orthologs in chicken and zebrafish, respectively, gathered in 28 groups of paralogs. Almost two thirds of the chicken orthologs and half of the zebrafish orthologs exhibited a relative expression ≥50% in testis. Finally, our focus on functional in silico data demonstrated that most of these genes were involved in the germ cell process, primarily in structure elaboration/maintenance and in acid nucleic metabolism. CONCLUSION: Our work confirms that the genes involved in germ cell development are highly conserved across evolution in vertebrates and invertebrates and display a high rate of conservation of preferential testicular expression among vertebrates. Among the genes highlighted in this study, three mouse genes (Lrrc46, Pabpc6 and Pkd2l1) have not previously been described in the testes, neither their zebrafish nor chicken orthologs. The phylogenetic approach developed in this study finally allows considering new testicular genes for further fundamental studies in vertebrates, including model species (mouse and zebrafish).


Assuntos
Galinhas/genética , Evolução Molecular , Testículo/metabolismo , Peixe-Zebra/genética , Animais , Drosophila melanogaster/genética , Masculino , Camundongos , Filogenia , Espermatogênese/genética , Testículo/citologia
5.
Adv Exp Med Biol ; 1166: 29-46, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31301044

RESUMO

Spermatogenesis is a highly complex biological process during which germ cells undergo recurrent rounds of DNA replication and cell division that may predispose to random mutational events. Hence, germ cells are vulnerable to the introduction of a range of de novo mutations, in particular chromosomal aberrations, point mutations and small indels. The main mechanisms through which mutations may occur during spermatogenesis are (i) errors in DNA replication, (ii) inefficient repair of non-replicative DNA damage between cell divisions and (iii) exposure to mutagens during lifetime. Any genetic alteration in the spermatozoa, if not repaired/eliminated, can be passed on to the offspring, potentially leading to malformations, chromosomal anomalies and monogenic diseases. Spontaneous de novo mutations tend to arise and accumulate with a higher frequency during testicular aging. In fact, there is an increased incidence of some chromosomal aberrations and a greater risk of congenital disorders, collectively termed paternal age effect (PAE), in children conceived by fathers with advanced age. PAE disorders are related to well-characterized de novo point mutations leading to a selective advantage on the mutant spermatogonial stem cells that cause a progressive enrichment over time of mutant spermatozoa in the testis.The purpose of this chapter is to provide a summary on the spontaneous genetic alterations that occur during spermatogenesis, focusing on their underlying mechanisms and their consequences in the offspring.


Assuntos
Células-Tronco Germinativas Adultas , Anormalidades Congênitas , Mutação , Idade Paterna , Espermatogênese , Anormalidades Congênitas/etiologia , Anormalidades Congênitas/genética , Humanos , Masculino , Espermatogênese/genética , Espermatozoides , Testículo
6.
J Dairy Sci ; 102(8): 7226-7236, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31202648

RESUMO

The mammalian Y chromosome gene families in the ampliconic region are expressed predominantly or exclusively in the testis, and their copy number variations (CNV) are significantly associated with male reproductive traits, suggesting they have important roles in spermatogenesis and testicular development. ZNF280AY (zinc finger protein 280A, Y-linked) is a member of the zinc finger protein family and has been identified as a bovid-specific Y-chromosome gene. The current study applied a reliable quantitative real-time PCR method to estimate the CNV of ZNF280AY in 715 bulls across 21 cattle breeds and to further investigate the association of the CNV of ZNF280AY with bull reproductive traits and ZNF280AY mRNA expression levels in adult testis. The results revealed that the median copy number of ZNF280AY was 47, and the copy number varied from 11 to 154, showing significant CNV between and within the investigated cattle breeds. In addition, all 715 bulls were classified into Y1, Y2, and Y3 lineage groups based on a rapid genotyping method described previously. Pairwise comparisons indicated that bulls belonging to the Y1 lineage had a significantly lower median copy number (40) than bulls belonging to the Y2 (52) and Y3 lineages (57). Association analysis revealed that the CNV of ZNF280AY was correlated negatively with the percentage of normal sperm and sperm concentration in Holstein bulls, whereas no significant correlation was observed with ejaculation volume, total sperm count, sperm motility, postthaw motility (PTM), and scrotal circumference in Holstein and Simmental bulls. Furthermore, no correlation was observed between ZNF280AY copy number and ZNF280AY mRNA expression levels in the testis. The current study suggests that the CNV of the ZNF280AY gene family is associated with male reproductive traits and may serve as a valuable marker for early bull fertility selection in Holstein breeding programs.


Assuntos
Bovinos/genética , Variações do Número de Cópias de DNA , Fertilidade/genética , Regulação da Expressão Gênica , Genes Ligados ao Cromossomo Y/genética , Reprodução/genética , Cromossomo Y/genética , Animais , Cruzamento , Bovinos/fisiologia , Marcadores Genéticos/genética , Genótipo , Masculino , Especificidade de Órgãos , Fenótipo , Reação em Cadeia da Polimerase em Tempo Real/veterinária , Especificidade da Espécie , Contagem de Espermatozoides/veterinária , Motilidade Espermática/genética , Espermatogênese/genética , Testículo/fisiologia , Dedos de Zinco/genética
7.
Cell Mol Life Sci ; 76(20): 4071-4102, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31254043

RESUMO

Mammalian spermatogenesis is a highly complex multi-step process sustained by a population of mitotic germ cells with self-renewal potential known as spermatogonial stem cells (SSCs). The maintenance and regulation of SSC function are strictly dependent on a supportive niche that is composed of multiple cell types. A detailed appreciation of the molecular mechanisms underpinning SSC activity and fate is of fundamental importance for spermatogenesis and male fertility. However, different models of SSC identity and spermatogonial hierarchy have been proposed and recent studies indicate that cell populations supporting steady-state germline maintenance and regeneration following damage are distinct. Importantly, dynamic changes in niche properties may underlie the fate plasticity of spermatogonia evident during testis regeneration. While formation of spermatogenic colonies in germ-cell-depleted testis upon transplantation is a standard assay for SSCs, differentiation-primed spermatogonial fractions have transplantation potential and this assay provides readout of regenerative rather than steady-state stem cell capacity. The characterisation of spermatogonial populations with regenerative capacity is essential for the development of clinical applications aimed at restoring fertility in individuals following germline depletion by genotoxic treatments. This review will discuss regulatory mechanisms of SSCs in homeostatic and regenerative testis and the conservation of these mechanisms between rodent models and man.


Assuntos
Fertilidade/genética , Infertilidade Masculina/genética , Espermatogênese/genética , Espermatogônias/citologia , Células-Tronco/citologia , Testículo/citologia , Animais , Diferenciação Celular , Regulação da Expressão Gênica , Homeostase/genética , Humanos , Infertilidade Masculina/metabolismo , Infertilidade Masculina/patologia , Infertilidade Masculina/terapia , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Modelos Genéticos , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Espermatogônias/metabolismo , Nicho de Células-Tronco/genética , Células-Tronco/metabolismo , Testículo/metabolismo
8.
Gene ; 706: 211-221, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31054360

RESUMO

Spermatogenesis is initiated when spermatogonial stem cells (SSCs) in the mature testes enter mitosis and trigger differentiation. Thus, spermatogenesis and the ability to maintain a continuous source of spermatogonia relies on the ability to differentiate SSCs. Many studies around the world have been performed to investigate the etiology of male infertility and recent studies have focused on the presence and identification of biomarkers. CD133 and CD24 are stem cell markers locating in the testis and spermatogonia. The aim of this study was to investigate the relationship of the CD133 and CD24 genes with spermatogenesis defects and examine them as a candidate a useful biomarker for azoospermia men. The association of CD133 and CD24 with spermatogenesis defects was investigated in patients with obstructive (O) and non-obstructive azoospermia (NOA). NOA cases were histopathologically classified into Hypospermatogenesis (HS), Maturation Arrest (MA), and Sertoli Cell Only Syndrome (SCO) groups. A qRT-PCR analysis of these genes was performed and protein expression levels were measured by Western blot analysis. CD133 expression in NOA group was found to be significantly different from OA and this was confirmed by immunohistochemistry and immunocytochemical assays. The qRT-PCR analysis revealed that gene expression of CD133 and CD24 had fold changes of 0.80 ±â€¯0.34 and 1.59 ±â€¯0.31 compared to controls, respectively in the HS group (p > 0.05) and 0.04 ±â€¯0.01 and 0.54 ±â€¯0.08 in the MA group (p < 0.05). In the SCO group, CD24 showed a 1.55 ±â€¯0.35-fold increase (p > 0.05). CD133 gene expression was not detected at the transcriptional level in the SCO group. Western blot analysis of CD133 protein expression revealed 1.83, 4.11, and 11.4-fold decreases in the HS, MA and SCO groups, respectively, compared to controls (p < 0.05). CD24 showed fold changes of 1.18, 0.38, (p < 0.05), and 0.89 in the HS, MA, and SCO groups, respectively. Immunohistochemical analysis of CD133 revealed moderate, partial staining in the HS group, compared to substantial, wide-spread staining in the OA group. No staining was detected in either the MA or SCO groups. The localization of CD133 in healthy sperm was determined to be prominent in the tail and partly expressed in the head by confocal laser scanning microscopy analysis. It was also found that the expression of CD133 protein was high in healthy commercially-sourced Sertoli cells as well as in the Sertoli cells of OA individuals. Data from this study show that CD133 exhibits different profiles in infertile patient groups and thus may be considered as a candidate biomarker. CD24 can be associated with blockage of germ cell maturation in the MA group. Curative protocols for spermatogenesis defects may be possible with the use of these markers and thus their identification is extremely valuable in terms of human reproductive health.


Assuntos
Antígeno AC133/genética , Azoospermia/genética , Antígeno CD24/genética , Antígeno AC133/fisiologia , Adulto , Azoospermia/fisiopatologia , Biomarcadores/metabolismo , Antígeno CD24/fisiologia , Humanos , Infertilidade Masculina/metabolismo , Masculino , Oligospermia/genética , Células de Sertoli/metabolismo , Espermatogênese/genética , Espermatogônias/metabolismo , Espermatozoides/metabolismo , Testículo/metabolismo
9.
Gene ; 706: 201-210, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31085275

RESUMO

The functional sperm is the key factor for species continuation. The process spermatogenesis, to produce mature sperm is quite complex. It begins with the proliferation and differentiation of spermatogonia, which develop from primary spermatocytes to secondary spermatocytes and round spermatids, which eventually develop into fertile mature sperm. Spermiogenesis is the latest stage of spermatogenesis, where the round spermatids undergo a series of dramatic morphological changes and extreme condensation of chromatin to construct mature sperm with species-specific shape. During spermiogenesis, chromatin remodeling is a unique progress. It leads the nucleosome from a histone-based structure to a mostly protamine-based configuration. The main events of chromatin remodeling are the replacement of histone by histone variants, hyperacetylation, transient DNA strand breaks and repair, variants by transition proteins and finally by protamines. In this review, we synthesize and summarize the current knowledge on the progress of chromatin remodeling during spermiogenesis. We straighten out the chronological order of chromatin remodeling and illustrate the possible regulation mechanisms of each step.


Assuntos
Montagem e Desmontagem da Cromatina/fisiologia , Cromatina/fisiologia , Espermatogênese/fisiologia , Animais , Cromatina/genética , Montagem e Desmontagem da Cromatina/genética , DNA/metabolismo , Histonas/metabolismo , Humanos , Masculino , Maturação do Esperma/genética , Espermátides/metabolismo , Espermatócitos/metabolismo , Espermatogênese/genética , Espermatozoides/metabolismo
10.
Nat Commun ; 10(1): 2278, 2019 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-31123254

RESUMO

Mammalian spermatogenesis is sustained by mitotic germ cells with self-renewal potential known as undifferentiated spermatogonia. Maintenance of undifferentiated spermatogonia and spermatogenesis is dependent on tightly co-ordinated transcriptional and post-transcriptional mechanisms. The RNA helicase DDX5 is expressed by spermatogonia but roles in spermatogenesis are unexplored. Using an inducible knockout mouse model, we characterise an essential role for DDX5 in spermatogonial maintenance and show that Ddx5 is indispensable for male fertility. We demonstrate that DDX5 regulates appropriate splicing of key genes necessary for spermatogenesis. Moreover, DDX5 regulates expression of cell cycle genes in undifferentiated spermatogonia post-transcriptionally and is required for cell proliferation and survival. DDX5 can also act as a transcriptional co-activator and we demonstrate that DDX5 interacts with PLZF, a transcription factor required for germline maintenance, to co-regulate select target genes. Combined, our data reveal a critical multifunctional role for DDX5 in regulating gene expression programmes and activity of undifferentiated spermatogonia.


Assuntos
RNA Helicases DEAD-box/metabolismo , Proteína com Dedos de Zinco da Leucemia Promielocítica/metabolismo , Processamento de RNA/fisiologia , Espermatogênese/genética , Espermatogônias/metabolismo , Animais , Ciclo Celular/genética , Proliferação de Células/genética , Técnicas de Cocultura , RNA Helicases DEAD-box/genética , Embrião de Mamíferos , Fertilidade/genética , Fibroblastos , Regulação da Expressão Gênica/fisiologia , Masculino , Camundongos , Camundongos Knockout , Modelos Animais , Cultura Primária de Células , Testículo/citologia
11.
Chemosphere ; 228: 709-720, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31071558

RESUMO

Silica nanoparticles (SiNPs) are found in the environmental particulate matter and have been proved to pose an adverse effect on fertility. However, the relationship between miRNA and apoptosis induced by SiNPs in spermatogenesis and its underlying mechanism remains confusing. Therefore, the present study was designed to investigate the toxic effects of SiNPs on spermatogenic cells mediated through miRNAs. Spermatocyte cells were divided into 0 µg/mL and 5 µg/mL SiNPs groups, and the cells were collected and analyzed after passaging for 1, 10, 20, and 30 generations. miRNA profile and mRNA profile of spermatocyte cells were measured after exposure to SiNPs for 30 generations. Further, mimics and inhibitors of miRNA were used to verify the relationship between miRNA and their predicted target genes in the 30th-generation cells. The results showed that the degree of cell apoptosis in the SiNPs group significantly increased in the 30th generation. After exposure to SiNPs for 30 generations, the expression of 15 miRNAs was altered, including 5 upregulated miRNAs and 10 downregulated miRNAs. Of the 15 miRNAs, miR-138 and miR-2861 were related to the death receptor pathway. The miR-2861 mimic could target to regulate the mRNA expression of fas/fasl/ripk1 and increase the protein expression of Fas/FasL/RIPK1/FADD/caspase-8/caspase-3 of spermatogenic cells in the 30th generation, while the miR-138 inhibitor could not. In conclusion, SiNPs could cause apoptosis of spermatocyte cells by inhibiting the expression of miRNA-2861, thereby resulting in the upregulation of mRNA expression of fas/fasl/ripk1 and activating the death receptor pathway of spermatocyte cells. miRNA-2861 could be considered a biomarker of the toxic effect of SiNPs on spermatocyte cells. The main finding: Silica nanoparticles induce apoptosis in spermatocyte cells through microRNA-2861 inhibition, thereby upregulating mRNA expression of fas/fasl/ripk1 and activating the death receptor pathway of spermatocyte cells.


Assuntos
MicroRNAs/genética , Nanopartículas/toxicidade , Receptores de Morte Celular/metabolismo , Dióxido de Silício/toxicidade , Espermatócitos/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Redes e Vias Metabólicas/efeitos dos fármacos , Camundongos , Nanopartículas/química , Receptores de Morte Celular/genética , Dióxido de Silício/química , Espermatócitos/metabolismo , Espermatócitos/patologia , Espermatogênese/efeitos dos fármacos , Espermatogênese/genética
12.
Chemosphere ; 230: 384-395, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31112861

RESUMO

Recently, environment contaminants including pesticides, fungicides, mycotoxin and others chemicals have been suggested to be responsible for the decline in the human spermatozoa quality especially motility and the increase in infertility rate. Chlorothalonil is used widely for protection of vegetables and crops because it is a broad spectrum fungicide. It has been reported that chronic occupational exposure to fungicides was associated with poor spermatozoa morphology in young men. The pubertal period is very important for the male reproductive system development due to spermatogonial cell proliferation, the expansion of meiotic and haploid germ cells. Although some investigations have studied the male reproductive toxicity of chlorothalonil, almost no studies focused on spermatogenesis. The aim of our current investigation was to explore the impacts of chlorothalonil on spermatogenesis and the underlying mechanisms. It demonstrates: i) chlorothalonil decreased boar spermatozoa motility in vitro and increased the cell apoptosis; ii) chlorothalonil inhibited mouse spermatogenesis in vivo; iii) chlorothalonil disturbed spermatogenesis through the disruption of estrogen receptor signalling; iv) chlorothalonil disrupted histone methylation and DNA methylation which might be through estrogen signalling pathways. Due to the over use or incorrect use, chlorothalonil might cause serious problems to human health, especially spermatogenesis. Therefore we strongly recommend that greater attention should be paid to this fungicide to minimise its impact on human health especially spermatogenesis.


Assuntos
Metilação de DNA/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Fungicidas Industriais/toxicidade , Histonas/metabolismo , Nitrilos/toxicidade , Receptores Estrogênicos/metabolismo , Espermatogênese/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Masculino , Camundongos Endogâmicos ICR , Transdução de Sinais , Motilidade Espermática/efeitos dos fármacos , Espermatogênese/genética , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo , Espermatozoides/patologia , Suínos
13.
PLoS Genet ; 15(5): e1008084, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31059511

RESUMO

The transition from mitotic to meiotic cell cycles is essential for haploid gamete formation and fertility. Stimulated by retinoic acid gene 8 (Stra8) is an essential gatekeeper of meiotic initiation in vertebrates; yet, the molecular role of STRA8 remains principally unknown. Here we demonstrate that STRA8 functions as a suppressor of autophagy during spermatogenesis in mice. Stra8-deficient germ cells fail to enter meiosis and present aberrant upregulation of autophagy-lysosome genes, commensurate with autophagy activation. Biochemical assays show that ectopic expression of STRA8 alone is sufficient to inhibit both autophagy induction and maturation. Studies also revealed that, Nr1d1, a nuclear hormone receptor gene, is upregulated in Stra8-deficient testes and that STRA8 binds to the Nr1d1 promoter, indicating that Nr1d1 is a direct target of STRA8 transcriptional repression. In addition, it was found that NR1D1 binds to the promoter of Ulk1, a gene essential for autophagy initiation, and that Nr1d1 is required for the upregulated Ulk1 expression in Stra8-deficient testes. Furthermore, both genetic deletion of Nr1d1 and pharmacologic inhibition of NR1D1 by its synthetic antagonist SR8278 exhibit rescuing effects on the meiotic initiation defects observed in Stra8-deficient male germ cells. Together, the data suggest a novel link between STRA8-mediated autophagy suppression and meiotic initiation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Fertilidade/genética , Meiose , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Espermatogênese/genética , Espermatozoides/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Animais , Autofagia/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Sequência de Bases , Regulação da Expressão Gênica no Desenvolvimento , Isoquinolinas/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/metabolismo , Regiões Promotoras Genéticas , Ligação Proteica , Espermatozoides/citologia , Testículo/citologia , Testículo/crescimento & desenvolvimento , Testículo/metabolismo , Tiofenos/farmacologia
14.
PLoS Genet ; 15(5): e1008028, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31071079

RESUMO

Intron gigantism, where genes contain megabase-sized introns, is observed across species, yet little is known about its purpose or regulation. Here we identify a unique gene expression program utilized for the proper expression of genes with intron gigantism. We find that two Drosophila genes with intron gigantism, kl-3 and kl-5, are transcribed in a spatiotemporal manner over the course of spermatocyte differentiation, which spans ~90 hours. The introns of these genes contain megabases of simple satellite DNA repeats that comprise over 99% of the gene loci, and these satellite-DNA containing introns are transcribed. We identify two RNA-binding proteins that specifically localize to kl-3 and kl-5 transcripts and are needed for the successful transcription or processing of these genes. We propose that genes with intron gigantism require a unique gene expression program, which may serve as a platform to regulate gene expression during cellular differentiation.


Assuntos
DNA Satélite/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Íntrons , Espermatócitos/metabolismo , Espermatogênese/genética , Animais , DNA Satélite/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/crescimento & desenvolvimento , Drosophila melanogaster/metabolismo , Éxons , Regulação da Expressão Gênica no Desenvolvimento , Masculino , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais , Espermatócitos/citologia , Espermatócitos/crescimento & desenvolvimento , Transcrição Genética , Cromossomo Y/química
16.
J Dairy Sci ; 102(7): 6263-6275, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31103297

RESUMO

Domestic yaks (Bos grunniens) and domestic Taurus cattle (Bos taurus) are closely related. An interesting phenomenon in interspecific crossings is male sterility in the F1 hybrid (yattle) and F2 backcross, with no late meiotic cells or spermatids in the seminiferous tubules. The mammalian Y chromosome is crucial for spermatogenesis and male fertility. This study investigated the copy number variations and mRNA of Y-transitional region genes TSPY2 (testis specific protein, Y-linked 2 and testis-specific Y-encoded protein 3-like) and PRAMEY (preferentially expressed antigen in melanoma, Y-linked), and Y-ampliconic region genes TSPY (testis-specific Y-encoded protein 1-like), ZNF280BY (zinc finger protein 280B, Y-linked) and HSFY (heat-shock transcription factor, Y-linked) in mature testes from Taurus cattle, yaks, and yattle. Phylogenetic trees divided 33 copies of TSPY into major 2 types (TSPY-T1 and TSPY-T2), 19 copies of TSPY2 into 2 types (TSPY2-T1 and T2), and 8 copies of PRAMEY into 4 types (PRAMEY-T1 to T4). Searching by the Basic Local Alignment Search Tool of the TSPY2 coding sequences in GenBank revealed that TSPY2 was conserved in Bovidae. The TSPY2-T2 sequences were absent, whereas PRAMEY-T2 and PRAMEY-T4 were amplified on the yak Y chromosome. The average copy numbers of TSPY-T2 and ZNF280BY were significantly different between cattle and yaks. The TSPY-T2, TSPY2, PRAMEY, ZNF280BY, and HSFY genes were uniquely or predominantly expressed in testes. Reverse-transcription quantitative PCR showed that the TSPY-T2, PRAMEY-T2, HSFY, ZNF280BY, protamine 1 (PRM1), and protamine 2 (PRM2) genes were almost not expressed in yattle. The PRM1 and PRM2 genes are used as positive markers for spermatozoa. Thus, our results showed that the genomic structure of the Y-transitional and Y-ampliconic region differed between Taurus cattle and yaks. Dysregulated expression of Y-ampliconic region genes TSPY-T2, HSPY, ZNF280BY, and Y-transitional region gene PRAMEY-T2 may be associated with hybrid male sterility in yattle.


Assuntos
Antígenos de Neoplasias/genética , Bovinos/genética , Proteínas de Ciclo Celular/genética , Ligação Genética/genética , Hibridização Genética/genética , Cromossomo Y/genética , Animais , Cruzamentos Genéticos , Variações do Número de Cópias de DNA , Expressão Gênica , Regulação da Expressão Gênica , Variação Genética/genética , Infertilidade Masculina/genética , Masculino , Filogenia , RNA Mensageiro/análise , Espermatogênese/genética , Testículo/metabolismo
17.
Yi Chuan ; 41(4): 271-284, 2019 Apr 20.
Artigo em Chinês | MEDLINE | ID: mdl-30992249

RESUMO

Polycomb repressive complex 1 (PRC1) is a class of epigenetic regulatory complexes that normally represses gene expression by catalyzing and/or recognizing chromatin modifications. PRC1 mainly functions in stem cell maintenance, cell differentiation, cell cycle regulation and related processes. PRC1 also have aberrant functions which has been implicated in many types of developmental diseases and cancers. Mammalian PRC1 complexes are divided into six subtypes based on their composition and function; subtypes include PRC1.1 to PRC1.6. Each PRC1 subtype regulates a unique collection of target genes. The PRC1.6 complex subtype plays key roles in specifically repressing transcription of genes controlling germ cell development in embryonic stem cells and other somatic cell types. Recent research demonstrates that the PRC1.6 complex is also crucial for the timely activation of the germ line of specific genes during spermatogenesis, which is essential for proper gonad development. In this review, we summarize the identification of molecular functions of each core component of the PRC1.6 complex including how it recognizes and represses germ line specific genes. We also update the biological roles of this complex in regulating the spatiotemporal expression of germ line specific genes during embryonic development, gonad development, and spermatogenesis. Lastly, the crosstalk between the PRC1.6 complex and the other main epigenetic regulatory mechanisms involved in controlling spermatogenesis is discussed. Our discussion of the PRC1.6 complex in regulating germ line specific genes informs the studies of molecular processes of spermatogenesis and contributes to the understanding of the pathogenic mechanisms of male infertility.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Células Germinativas/crescimento & desenvolvimento , Complexo Repressor Polycomb 1/genética , Espermatogênese/genética , Animais , Diferenciação Celular , Células-Tronco Embrionárias/citologia , Epigênese Genética , Masculino , Análise Espaço-Temporal
18.
J Toxicol Sci ; 44(4): 257-271, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30944279

RESUMO

Vitamin A and its derivatives contribute to many physiological processes, including vision, neural differentiation, and reproduction. Vitamin A deficiency causes early cessation of spermatogenesis, characterized by a marked depletion of germ cells. However, there has been no clear understanding about the role of chronic intake of vitamin A excess (VAE) in spermatogenesis. The objective of this study was to investigate whether chronic intake of VAE diet causes arrest of spermatogenesis. To examine the effects of VAE on spermatogenesis, we used ICR male mice fed with control (AIN-93G purified diet: 4 IU/g) diet or VAE (modified AIN-93G diet with VAE: 1,000 IU/g) diet for 7 weeks (from 3 to 10 weeks of age). At 10 weeks of age, the retinol concentration in the testes of VAE mice was significantly higher than that of control mice. Testicular cross sections from control mice contained a normal array of germ cells, while the seminiferous tubules from VAE mice exhibited varying degrees of testicular degeneration. Daily sperm production in VAE testes was dramatically decreased compared to that in control testes. Sperm viability, motility, and morphology were also impaired in VAE mice. Furthermore, we examined the effects of VAE on the expression of genes involved in retinoid signaling and spermatogenesis to determine the underlying molecular mechanisms. Therefore, we are the first to present results describing the long-term dietary intake of VAE impairs spermatogenesis using a mouse model.


Assuntos
Exposição Dietética/efeitos adversos , Hipervitaminose A/etiologia , Hipervitaminose A/fisiopatologia , Espermatogênese/efeitos dos fármacos , Vitamina A/administração & dosagem , Vitamina A/efeitos adversos , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Hipervitaminose A/metabolismo , Masculino , Camundongos Endogâmicos ICR , Gravidez , Retinoides , Transdução de Sinais/genética , Motilidade Espermática/efeitos dos fármacos , Espermatogênese/genética , Espermatozoides/efeitos dos fármacos , Espermatozoides/patologia , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testículo/patologia , Fatores de Tempo , Vitamina A/metabolismo
19.
Ecotoxicol Environ Saf ; 176: 242-249, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-30939404

RESUMO

Pesticides, fungicides are reportedly involved in a decline in spermatozoa quality, especially motility, and a consequent increase in the rate of infertility. Fungicide carbendazim (CBZ) is widely used in agriculture and other aspects. Although CBZ is known to disrupt spermatogenesis, causing a decrease in spermatozoa concentration and motility, the mechanisms are not fully understood. We aimed to further explore the underlying mechanisms of CBZ disruption of spermatogenesis. Pubertal mice were exposed to low doses (0.1, 1 and 10 mg/kg body weight) of CBZ for 5 weeks, then many factors related to spermatogenesis have been explored. It was found that 0.1-10 mg/kg body weight of CBZ exposure decreased mouse sperm motility and concentration, diminished the important protein factors (VASA, PGK2, B-Amy and CREM) for spermatogenesis, reduced sperm protein acrosin level, disrupted very vital epigenetic factors H3K27, 5 mC and 5 hmC. Furthermore, CBZ exposure damaged estrogen receptor alpha (ERα) pathway by decreased the protein levels of ERα and its targets PI3K and AKT. In summary low doses of CBZ exposure disrupted mouse spermatogenesis through estrogen receptor signaling; and that histone methylation and DNA methylation might play vital roles in CBZ disturbance of spermatogenesis through intertwining with estrogen signaling pathways. CBZ from the contamination in environment or food chain poses a serious threat to the normal development of spermatozoa. Therefore we strongly recommend to minimise the use of CBZ since it causes the severe issues on spermatogenesis.


Assuntos
Benzimidazóis/toxicidade , Carbamatos/toxicidade , Metilação de DNA/efeitos dos fármacos , Receptor alfa de Estrogênio/metabolismo , Histonas/metabolismo , Espermatogênese/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Estrogênios/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Contagem de Espermatozoides , Motilidade Espermática/efeitos dos fármacos , Espermatogênese/genética , Espermatozoides/metabolismo
20.
Gen Comp Endocrinol ; 280: 123-133, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31009604

RESUMO

Receptors for follicle-stimulating hormone (Fshr), luteinizing hormone (Lhcgr1 and Lhcgr2) and androgens (Ara and Arb) transduce the hormonal signals that coordinate spermatogenesis, but the factors that regulate the abundance of these transducers in fish testes remain little-understood. To mend this paucity of information, we first determined changes in transcript abundance for these receptors (fshr, lhcgr1, ara and arb) during spermatogenesis induced by human chorionic gonadotropin (hCG) injection in the eel, Anguilla australis. We related our findings to testicular production of the fish androgen, 11-ketotestosterone (11-KT), and to the levels of the transcripts encoding steroidogenic acute regulatory protein (star) and 11ß-hydroxylase (cyp11b), and subsequently evaluated the effects of hCG or 11-KT on mRNA levels of these target genes in vitro. Testicular 11-KT production was greatly increased by hCG treatment, both in vivo and in vitro, and associated with up-regulation of star and cyp11b transcripts. In situ hybridization indicated that testicular fshr mRNA levels were higher in the early stages of hCG-induced spermatogenesis, while lhcgr1 transcripts were most abundant later, once spermatids were observed. In vitro experiments further showed that hCG and its steroidal mediator 11-KT significantly increased fshr transcript abundance. These data provide new angles on the interactions between gonadotropin and androgen signaling during early spermatogenesis. Increases in levels of 11-KT following hCG injection elevated testicular fshr mRNA levels augmenting Fsh sensitivity in the testis. This evidence is suggestive of a positive feedback loop between gonadotropins and 11-KT that may be key to regulating early spermatogenesis in fish.


Assuntos
Anguilla/genética , Regulação da Expressão Gênica , Receptores Androgênicos/genética , Receptores da Gonadotropina/genética , Testículo/metabolismo , Androgênios/metabolismo , Anguilla/sangue , Animais , Gonadotropina Coriônica/administração & dosagem , Gonadotropina Coriônica/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Androgênicos/metabolismo , Receptores do FSH/genética , Receptores do FSH/metabolismo , Receptores da Gonadotropina/metabolismo , Receptores do LH/genética , Receptores do LH/metabolismo , Espermatogênese/efeitos dos fármacos , Espermatogênese/genética , Esteroide 11-beta-Hidroxilase/genética , Esteroide 11-beta-Hidroxilase/metabolismo , Testículo/efeitos dos fármacos , Testosterona/análogos & derivados , Testosterona/sangue
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA