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International Journal of Molecular... Oct 2020Several studies proposed the importance of zinc ion in male fertility. Here, we describe the properties, roles and cellular mechanisms of action of Zn in spermatozoa,... (Review)
Review
Several studies proposed the importance of zinc ion in male fertility. Here, we describe the properties, roles and cellular mechanisms of action of Zn in spermatozoa, focusing on its involvement in sperm motility, capacitation and acrosomal exocytosis, three functions that are crucial for successful fertilization. The impact of zinc supplementation on assisted fertilization techniques is also described. The impact of zinc on sperm motility has been investigated in many vertebrate and invertebrate species. It has been reported that Zn in human seminal plasma decreases sperm motility and that Zn removal enhances motility. Reduction in the intracellular concentration of Zn during epididymal transit allows the development of progressive motility and the subsequent hyper activated motility during sperm capacitation. Extracellular Zn affects intracellular signaling pathways through its interaction with the Zn sensing receptor (ZnR), also named GPR39. This receptor was found in the sperm tail and the acrosome, suggesting the possible involvement of Zn in sperm motility and acrosomal exocytosis. Our studies showed that Zn stimulates bovine sperm acrosomal exocytosis, as well as human sperm hyper-activated motility, were both mediated by GPR39. Zn binds and activates GPR39, which activates the trans-membrane-adenylyl-cyclase (tmAC) to catalyze cAMP production. The NHE (Na/H-exchanger) is activated by cAMP, leading in increased pHi and activation of the sperm-specific Ca channel CatSper, resulting in an increase in [Ca], which, together with HCO, activates the soluble adenylyl-cyclase (sAC). The increase in [cAMP] activates protein kinase A (PKA), followed by activation of the Src-epidermal growth factor receptor-Pphospholipase C (Src-EGFR-PLC) cascade, resulting in inositol-triphosphate (IP) production, which mobilizes Ca from the acrosome, causing a further increase in [Ca] and the development of hyper-activated motility. PKA also activates phospholipase D1 (PLD1), leading to F-actin formation during capacitation. Prior to the acrosomal exocytosis, PLC induces phosphadidylinositol-4,5-bisphosphate (PIP) hydrolysis, leading to the release of the actin-severing protein gelsolin to the cytosol, which is activated by Ca, resulting in F-actin breakdown and the occurrence of acrosomal exocytosis.
Topics: Acrosome; Animals; Fertility; Humans; Male; Reproductive Techniques, Assisted; Sperm Capacitation; Sperm Motility; Spermatozoa; Zinc
PubMed: 33096823
DOI: 10.3390/ijms21207796 -
Cell Jun 2023Sperm motility is crucial to reproductive success in sexually reproducing organisms. Impaired sperm movement causes male infertility, which is increasing globally. Sperm...
Sperm motility is crucial to reproductive success in sexually reproducing organisms. Impaired sperm movement causes male infertility, which is increasing globally. Sperm are powered by a microtubule-based molecular machine-the axoneme-but it is unclear how axonemal microtubules are ornamented to support motility in diverse fertilization environments. Here, we present high-resolution structures of native axonemal doublet microtubules (DMTs) from sea urchin and bovine sperm, representing external and internal fertilizers. We identify >60 proteins decorating sperm DMTs; at least 15 are sperm associated and 16 are linked to infertility. By comparing DMTs across species and cell types, we define core microtubule inner proteins (MIPs) and analyze evolution of the tektin bundle. We identify conserved axonemal microtubule-associated proteins (MAPs) with unique tubulin-binding modes. Additionally, we identify a testis-specific serine/threonine kinase that links DMTs to outer dense fibers in mammalian sperm. Our study provides structural foundations for understanding sperm evolution, motility, and dysfunction at a molecular level.
Topics: Male; Animals; Cattle; Sperm Tail; Sperm Motility; Semen; Microtubules; Axoneme; Spermatozoa; Mammals
PubMed: 37327785
DOI: 10.1016/j.cell.2023.05.026 -
Cellular and Molecular Life Sciences :... Jun 2020The core axoneme structure of both the motile cilium and sperm tail has the same ultrastructural 9 + 2 microtubular arrangement. Thus, it can be expected that... (Review)
Review
The core axoneme structure of both the motile cilium and sperm tail has the same ultrastructural 9 + 2 microtubular arrangement. Thus, it can be expected that genetic defects in motile cilia also have an effect on sperm tail formation. However, recent studies in human patients, animal models and model organisms have indicated that there are differences in components of specific structures within the cilia and sperm tail axonemes. Primary ciliary dyskinesia (PCD) is a genetic disease with symptoms caused by malfunction of motile cilia such as chronic nasal discharge, ear, nose and chest infections and pulmonary disease (bronchiectasis). Half of the patients also have situs inversus and in many cases male infertility has been reported. PCD genes have a role in motile cilia biogenesis, structure and function. To date mutations in over 40 genes have been identified cause PCD, but the exact effect of these mutations on spermatogenesis is poorly understood. Furthermore, mutations in several additional axonemal genes have recently been identified to cause a sperm-specific phenotype, termed multiple morphological abnormalities of the sperm flagella (MMAF). In this review, we discuss the association of PCD genes and other axonemal genes with male infertility, drawing particular attention to possible differences between their functions in motile cilia and sperm tails.
Topics: Animals; Cilia; Ciliary Motility Disorders; Humans; Infertility, Male; Male; Mutation; Spermatozoa
PubMed: 31781811
DOI: 10.1007/s00018-019-03389-7 -
Molecular and Cellular Endocrinology Dec 2020Centrioles are eukaryotic subcellular structures that produce and regulate massive cytoskeleton superstructures. They form centrosomes and cilia, regulate new centriole... (Review)
Review
Centrioles are eukaryotic subcellular structures that produce and regulate massive cytoskeleton superstructures. They form centrosomes and cilia, regulate new centriole formation, anchor cilia to the cell, and regulate cilia function. These basic centriolar functions are executed in sperm cells during their amplification from spermatogonial stem cells during their differentiation to spermatozoa, and finally, after fertilization, when the sperm fuses with the egg. However, sperm centrioles exhibit many unique characteristics not commonly observed in other cell types, including structural remodeling, centriole-flagellum transition zone migration, and cell membrane association during meiosis. Here, we discuss five roles of sperm centrioles: orchestrating early spermatogenic cell divisions, forming the spermatozoon flagella, linking the spermatozoon head and tail, controlling sperm tail beating, and organizing the cytoskeleton of the zygote post-fertilization. We present the historic discovery of the centriole as a sperm factor that initiates embryogenesis, and recent genetic studies in humans and other mammals evaluating the current evidence for the five functions of sperm centrioles. We also examine information connecting the various sperm centriole functions to distinct clinical phenotypes. The emerging picture is that centrioles are essential sperm components with remarkable functional diversity and specialization that will require extensive and in-depth future studies.
Topics: Animals; Cell Differentiation; Centrioles; Embryonic Development; Fertilization; Humans; Male; Meiosis; Spermatozoa
PubMed: 32810575
DOI: 10.1016/j.mce.2020.110987 -
Cell Sep 2023Nucleosomes block access to DNA methyltransferase, unless they are remodeled by DECREASE in DNA METHYLATION 1 (DDM1), a Snf2-like master regulator of epigenetic...
Nucleosomes block access to DNA methyltransferase, unless they are remodeled by DECREASE in DNA METHYLATION 1 (DDM1), a Snf2-like master regulator of epigenetic inheritance. We show that DDM1 promotes replacement of histone variant H3.3 by H3.1. In ddm1 mutants, DNA methylation is partly restored by loss of the H3.3 chaperone HIRA, while the H3.1 chaperone CAF-1 becomes essential. The single-particle cryo-EM structure at 3.2 Å of DDM1 with a variant nucleosome reveals engagement with histone H3.3 near residues required for assembly and with the unmodified H4 tail. An N-terminal autoinhibitory domain inhibits activity, while a disulfide bond in the helicase domain supports activity. DDM1 co-localizes with H3.1 and H3.3 during the cell cycle, and with the DNA methyltransferase MET1, but is blocked by H4K16 acetylation. The male germline H3.3 variant MGH3/HTR10 is resistant to remodeling by DDM1 and acts as a placeholder nucleosome in sperm cells for epigenetic inheritance.
Topics: Chromatin Assembly and Disassembly; DNA; DNA Methylation; DNA Modification Methylases; Epigenesis, Genetic; Histones; Nucleosomes; Semen; Arabidopsis; Arabidopsis Proteins
PubMed: 37643610
DOI: 10.1016/j.cell.2023.08.001 -
Science Advances Oct 2022Centrosomal protein dysfunction might cause ciliopathies. However, the role of centrosomal proteins in male infertility remains poorly defined. Here, we identified a...
Centrosomal protein dysfunction might cause ciliopathies. However, the role of centrosomal proteins in male infertility remains poorly defined. Here, we identified a pathogenic splicing mutation in in male infertile patients with severely reduced sperm number and motility, and the typical multiple morphological abnormalities of the sperm flagella phenotype. We further created knockout mice, which showed an extremely low sperm count, completely aberrant sperm morphology, and approximately null sperm motility. The infertility of the patients and knockout mice could not be rescued by an intracytoplasmic sperm injection treatment. Mechanistically, CEP78 might regulate USP16 expression, which further stabilizes Tektin levels via the ubiquitination pathway. knockout mice also exhibited impairments in retina and outer hair cells of the cochlea. Collectively, our findings identified nonfunctional CEP78 as an indispensable factor contributing to male infertility and revealed a role for this gene in regulating retinal and outer hair cell function in mice.
Topics: Animals; Humans; Male; Mice; Cell Cycle Proteins; Infertility, Male; Mice, Knockout; Mutation; Semen; Sperm Motility; Sperm Tail; Spermatozoa
PubMed: 36206347
DOI: 10.1126/sciadv.abn0968 -
American Journal of Human Genetics Jan 2022Asthenoteratozoospermia, defined as reduced sperm motility and abnormal sperm morphology, is a disorder with considerable genetic heterogeneity. Although previous...
Asthenoteratozoospermia, defined as reduced sperm motility and abnormal sperm morphology, is a disorder with considerable genetic heterogeneity. Although previous studies have identified several asthenoteratozoospermia-associated genes, the etiology remains unknown for the majority of affected men. Here, we performed whole-exome sequencing on 497 unrelated men with asthenoteratozoospermia and identified DNHD1 bi-allelic variants from eight families (1.6%). All detected variants were predicted to be deleterious via multiple bioinformatics tools. Hematoxylin and eosin (H&E) staining revealed that individuals with bi-allelic DNHD1 variants presented striking abnormalities of the flagella; transmission electron microscopy (TEM) further showed flagellar axoneme defects, including central pair microtubule (CP) deficiency and mitochondrial sheath (MS) malformations. In sperm from fertile men, DNHD1 was localized to the entire flagella of the normal sperm; however, it was nearly absent in the flagella of men with bi-allelic DNHD1 variants. Moreover, abundance of the CP markers SPAG6 and SPEF2 was significantly reduced in spermatozoa from men harboring bi-allelic DNHD1 variants. In addition, Dnhd1 knockout male mice (Dnhd1) exhibited asthenoteratozoospermia and infertility, a finding consistent with the sperm phenotypes present in human subjects with DNHD1 variants. The female partners of four out of seven men who underwent intracytoplasmic sperm injection therapy subsequently became pregnant. In conclusion, our study showed that bi-allelic DNHD1 variants cause asthenoteratozoospermia, a finding that provides crucial insights into the biological underpinnings of this disorder and should assist with counseling of affected individuals.
Topics: Alleles; Animals; Asthenozoospermia; Axoneme; Computational Biology; DNA Mutational Analysis; Disease Models, Animal; Dyneins; Flagella; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Infertility, Male; Male; Mice; Mice, Knockout; Mitochondria; Mutation; Pedigree; Phenotype; Semen Analysis; Sperm Tail; Exome Sequencing
PubMed: 34932939
DOI: 10.1016/j.ajhg.2021.11.022 -
Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility.American Journal of Human Genetics Feb 2021Asthenoteratozoospermia characterized by multiple morphological abnormalities of the flagella (MMAF) has been identified as a sub-type of male infertility. Recent...
Asthenoteratozoospermia characterized by multiple morphological abnormalities of the flagella (MMAF) has been identified as a sub-type of male infertility. Recent progress has identified several MMAF-associated genes with an autosomal recessive inheritance in human affected individuals, but the etiology in approximately 40% of affected individuals remains unknown. Here, we conducted whole-exome sequencing (WES) and identified hemizygous missense variants in the X-linked CFAP47 in three unrelated Chinese individuals with MMAF. These three CFAP47 variants were absent in human control population genome databases and were predicted to be deleterious by multiple bioinformatic tools. CFAP47 encodes a cilia- and flagella-associated protein that is highly expressed in testis. Immunoblotting and immunofluorescence assays revealed obviously reduced levels of CFAP47 in spermatozoa from all three men harboring deleterious missense variants of CFAP47. Furthermore, WES data from an additional cohort of severe asthenoteratozoospermic men originating from Australia permitted the identification of a hemizygous Xp21.1 deletion removing the entire CFAP47 gene. All men harboring hemizygous CFAP47 variants displayed typical MMAF phenotypes. We also generated a Cfap47-mutated mouse model, the adult males of which were sterile and presented with reduced sperm motility and abnormal flagellar morphology and movement. However, fertility could be rescued by the use of intra-cytoplasmic sperm injections (ICSIs). Altogether, our experimental observations in humans and mice demonstrate that hemizygous mutations in CFAP47 can induce X-linked MMAF and asthenoteratozoospermia, for which good ICSI prognosis is suggested. These findings will provide important guidance for genetic counseling and assisted reproduction treatments.
Topics: Animals; Asthenozoospermia; Cohort Studies; Female; Gene Deletion; Genes, X-Linked; Hemizygote; Humans; Infertility, Male; Male; Mice, Inbred C57BL; Mutation; Mutation, Missense; Pedigree; Phenotype; Sperm Injections, Intracytoplasmic; Sperm Motility; Sperm Tail; Spermatozoa; Exome Sequencing; Mice
PubMed: 33472045
DOI: 10.1016/j.ajhg.2021.01.002 -
The World Journal of Men's Health Jan 2020Microtubules are the prime component of the cytoskeleton along with microfilaments. Being vital for organelle transport and cellular divisions during spermatogenesis and... (Review)
Review
Microtubules are the prime component of the cytoskeleton along with microfilaments. Being vital for organelle transport and cellular divisions during spermatogenesis and sperm motility process, microtubules ascertain functional capacity of sperm. Also, microtubule based structures such as axoneme and manchette are crucial for sperm head and tail formation. This review (a) presents a concise, yet detailed structural overview of the microtubules, (b) analyses the role of microtubule structures in various male reproductive functions, and (c) presents the association of microtubular dysfunctions with male infertility. Considering the immense importance of microtubule structures in the formation and maintenance of physiological functions of sperm cells, this review serves as a scientific trigger in stimulating further male infertility research in this direction.
PubMed: 30350487
DOI: 10.5534/wjmh.180066 -
Nature Communications Aug 2021The sperm head-to-tail coupling apparatus (HTCA) ensures sperm head-tail integrity while defective HTCA causes acephalic spermatozoa, rendering males infertile. Here, we...
The sperm head-to-tail coupling apparatus (HTCA) ensures sperm head-tail integrity while defective HTCA causes acephalic spermatozoa, rendering males infertile. Here, we show that CENTLEIN is indispensable for HTCA integrity and function, and that inactivation of CENTLEIN in mice leads to sperm decapitation and male sterility. We demonstrate that CENTLEIN directly interacts with both SUN5 and PMFBP1, two proteins localized in the HTCA and related with acephalic spermatozoa syndrome. We find that the absence of Centlein sets SUN5 and PMFBP1 apart, the former close to the sperm head and the latter in the decapitated tail. We show that lack of Sun5 results in CENTLEIN and PMFBP1 left in the decapitated tail, while disruption of Pmfbp1 results in SUN5 and CENTLEIN left on the detached sperm head. These results demonstrate that CENTLEIN cooperating with SUN5 and PMFBP1 participates in the HTCA assembly and integration of sperm head to the tail, indicating that impairments of CENTLEIN might be associated with acephalic spermatozoa syndrome in humans.
Topics: Animals; Cell Cycle Proteins; Cells, Cultured; Cytoskeletal Proteins; HEK293 Cells; Humans; Infertility, Male; Male; Membrane Proteins; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Knockout; Mutation; Protein Binding; Sperm Head; Sperm Tail; Spermatozoa; Teratozoospermia; Mice
PubMed: 34389728
DOI: 10.1038/s41467-021-25227-w