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Genes Jan 2019The near complete replacement of somatic chromatin in spermatids is, perhaps, the most striking nuclear event known to the eukaryotic domain. The process is far from... (Review)
Review
The near complete replacement of somatic chromatin in spermatids is, perhaps, the most striking nuclear event known to the eukaryotic domain. The process is far from being fully understood, but research has nevertheless unraveled its complexity as an expression of histone variants and post-translational modifications that must be finely orchestrated to promote the DNA topological change and compaction provided by the deposition of protamines. That this major transition may not be genetically inert came from early observations that transient DNA strand breaks were detected in situ at chromatin remodeling steps. The potential for genetic instability was later emphasized by our demonstration that a significant number of DNA double-strand breaks (DSBs) are formed and then repaired in the haploid context of spermatids. The detection of DNA breaks by 3'OH end labeling in the whole population of spermatids suggests that a reversible enzymatic process is involved, which differs from canonical apoptosis. We have set the stage for a better characterization of the genetic impact of this transition by showing that post-meiotic DNA fragmentation is conserved from human to yeast, and by providing tools for the initial mapping of the genome-wide DSB distribution in the mouse model. Hence, the molecular mechanism of post-meiotic DSB formation and repair in spermatids may prove to be a significant component of the well-known male mutation bias. Based on our recent observations and a survey of the literature, we propose that the chromatin remodeling in spermatids offers a proper context for the induction of de novo polymorphism and structural variations that can be transmitted to the next generation.
Topics: Animals; Chromatin Assembly and Disassembly; Chromosomal Instability; Male; Mutation Rate; Spermatids; Spermatogenesis
PubMed: 30646585
DOI: 10.3390/genes10010040 -
Archives of Histology and Cytology Nov 2004A combination of exogenous contractile forces generated by a stack of F-actin-containing hoops embracing the apical region of the elongating spermatid nucleus and an... (Review)
Review
A combination of exogenous contractile forces generated by a stack of F-actin-containing hoops embracing the apical region of the elongating spermatid nucleus and an endogenous modulating mechanism dependent on the spermatid-containing acrosome-acroplaxome-manchette complex may play a cooperative role in the shaping of the spermatid head. In addition, the manchette is a key element in the transport of vesicles and macromolecules to the centrosome and developing spermatid tails as well as in nucleocytoplasmic transport. The proposed model of spermatid head shaping is based on: 1) currently known structural and molecular components of the F-actin hoops, the main cytoskeletal element of the Sertoli cell ectoplasmic specializations; 2) the molecular features of acrosome biogenesis; 3) the assembly of a subacrosomal cytoskeletal plate called the acroplaxome; and 4) the spatial relationship of the acrosome-acroplaxome complex with the manchette, a transient microtubular/actin-containing structure. During acrosome biogenesis, the acroplaxome becomes the nucleation site to which Golgi-derived proacrosomal vescicles tether and fuse. The acroplaxome has at least two functions: it anchors the developing acrosome to the elongating spermatid head. It may also provide a mechanical scaffolding plate during the shaping of the spermatid nucleus. The plate is stabilized by a marginal ring with junctional complex characteristics, adjusting to exogenous clutching forces generated by the stack of Sertoli cell F-actin-containing hoops applied to the elongating spermatid head. A tubulobulbar complex, formed by cytoplasmic processes protruding from the elongating spermatid head extending into the adjacent Sertoli cell, is located at the concave side of the spermatid head. The tubulobulbar complex might provide stabilizing conditions, together with the actin-afadin-nectin-2/nectin-3 adhesion unit, to enable sustained and balanced clutching exogenous forces applied during the elongation of the spermatid head.
Topics: Acrosome; Actins; Animals; Cell Nucleus; Cytoplasmic Vesicles; Cytoskeleton; Golgi Apparatus; Humans; Male; Microtubules; Sertoli Cells; Spermatids; Spermatogenesis
PubMed: 15700535
DOI: 10.1679/aohc.67.271 -
ELife Mar 2020Mammalian spermiogenesis is a remarkable cellular transformation, during which round spermatids elongate into chromatin-condensed spermatozoa. The signaling pathways...
Mammalian spermiogenesis is a remarkable cellular transformation, during which round spermatids elongate into chromatin-condensed spermatozoa. The signaling pathways that coordinate this process are not well understood, and we demonstrate here that homeodomain-interacting protein kinase 4 (HIPK4) is essential for spermiogenesis and male fertility in mice. HIPK4 is predominantly expressed in round and early elongating spermatids, and knockout males are sterile, exhibiting phenotypes consistent with oligoasthenoteratozoospermia. mutant sperm have reduced oocyte binding and are incompetent for in vitro fertilization, but they can still produce viable offspring via intracytoplasmic sperm injection. Optical and electron microscopy of HIPK4-null male germ cells reveals defects in the filamentous actin (F-actin)-scaffolded acroplaxome during spermatid elongation and abnormal head morphologies in mature spermatozoa. We further observe that HIPK4 overexpression induces branched F-actin structures in cultured fibroblasts and that HIPK4 deficiency alters the subcellular distribution of an F-actin capping protein in the testis, supporting a role for this kinase in cytoskeleton remodeling. Our findings establish HIPK4 as an essential regulator of sperm head shaping and potential target for male contraception.
Topics: Acrosome; Actins; Animals; Fertility; Fluorescent Antibody Technique; Gene Expression Regulation, Developmental; Male; Mice; Mice, Knockout; Models, Biological; Mutation; Phenotype; Protein Binding; Protein Serine-Threonine Kinases; Signal Transduction; Spermatids; Spermatogenesis; Spermatozoa
PubMed: 32163033
DOI: 10.7554/eLife.50209 -
Seminars in Cell & Developmental Biology Sep 2018In adult mammalian testes, spermatids, most notably step 17-19 spermatids in stage IV-VIII tubules, are aligned with their heads pointing toward the basement membrane... (Review)
Review
In adult mammalian testes, spermatids, most notably step 17-19 spermatids in stage IV-VIII tubules, are aligned with their heads pointing toward the basement membrane and their tails toward the tubule lumen. On the other hand, these polarized spermatids also align across the plane of seminiferous epithelium, mimicking planar cell polarity (PCP) found in other hair cells in cochlea (inner ear). This orderly alignment of developing spermatids during spermiogenesis is important to support spermatogenesis, such that the maximal number of developing spermatids can be packed and supported by a fixed population of differentiated Sertoli cells in the limited space of the seminiferous epithelium in adult testes. In this review, we provide emerging evidence to demonstrate spermatid PCP in the seminiferous epithelium to support spermatogenesis. We also review findings in the field regarding the biology of spermatid cellular polarity (e.g., head-tail polarity and apico-basal polarity) and its inter-relationship to spermatid PCP. Furthermore, we also provide a hypothetical concept on the importance of PCP proteins in endocytic vesicle-mediated protein trafficking events to support spermatogenesis through protein endocytosis and recycling.
Topics: Animals; Cell Polarity; Humans; Male; Sertoli Cells; Signal Transduction; Spermatids; Spermatogenesis; Testis
PubMed: 28923514
DOI: 10.1016/j.semcdb.2017.09.008 -
Development (Cambridge, England) Jun 2021Spermatogenesis is precisely controlled by complex gene-expression programs. During mammalian male germ-cell development, a crucial feature is the repression of...
Spermatogenesis is precisely controlled by complex gene-expression programs. During mammalian male germ-cell development, a crucial feature is the repression of transcription before spermatid elongation. Previously, we discovered that the RNA-binding protein EWSR1 plays an important role in meiotic recombination in mouse, and showed that EWSR1 is highly expressed in late meiotic cells and post-meiotic cells. Here, we used an Ewsr1 pachytene stage-specific knockout mouse model to study the roles of Ewsr1 in late meiotic prophase I and in spermatozoa maturation. We show that loss of EWSR1 in late meiotic prophase I does not affect proper meiosis completion, but does result in defective spermatid elongation and chromocenter formation in the developing germ cells. As a result, male mice lacking EWSR1 after pachynema are sterile. We found that, in Ewsr1 CKO round spermatids, transition from a meiotic gene-expression program to a post-meiotic and spermatid gene expression program related to DNA condensation is impaired, suggesting that EWSR1 plays an important role in regulation of spermiogenesis-related mRNA synthesis necessary for spermatid differentiation into mature sperm.
Topics: Animals; Gene Expression Regulation, Developmental; Male; Meiosis; Meiotic Prophase I; Mice; Mice, Knockout; RNA-Binding Protein EWS; Spermatids; Spermatogenesis; Spermatozoa
PubMed: 34100066
DOI: 10.1242/dev.199414 -
Seminars in Cell & Developmental Biology Sep 2018Non-receptor Src family kinases (SFKs), most notably c-Src and c-Yes, are recently shown to be expressed by Sertoli and/or germ cells in adult rat testes. Studies have... (Review)
Review
Non-receptor Src family kinases (SFKs), most notably c-Src and c-Yes, are recently shown to be expressed by Sertoli and/or germ cells in adult rat testes. Studies have shown that SFKs are involved in modulating the cell cytoskeletal function, and involved in endocytic vesicle-mediated protein endocytosis, transcytosis and/or recycling as well as intracellular protein degradation events. Furthermore, a knockdown to SFKs, in particular c-Yes, has shown to induce defects in spermatid polarity. These findings, coupled with emerging evidence in the field, thus prompt us to critically evaluate them to put forth a developing concept regarding the role of SFKs and cell polarity, which will become a basis to design experiments for future investigations.
Topics: Animals; Cell Polarity; Cytoskeleton; Humans; Male; Sertoli Cells; Spermatids; Testis; src-Family Kinases
PubMed: 29174914
DOI: 10.1016/j.semcdb.2017.11.024 -
Development (Cambridge, England) May 2023Unique chromatin remodeling factors orchestrate dramatic changes in nuclear morphology during differentiation of the mature sperm head. A crucial step in this process is...
Unique chromatin remodeling factors orchestrate dramatic changes in nuclear morphology during differentiation of the mature sperm head. A crucial step in this process is histone-to-protamine exchange, which must be executed correctly to avoid sperm DNA damage, embryonic lethality and male sterility. Here, we define an essential role for the histone methyltransferase DOT1L in the histone-to-protamine transition. We show that DOT1L is abundantly expressed in mouse meiotic and postmeiotic germ cells, and that methylation of histone H3 lysine 79 (H3K79), the modification catalyzed by DOT1L, is enriched in developing spermatids in the initial stages of histone replacement. Elongating spermatids lacking DOT1L fail to fully replace histones and exhibit aberrant protamine recruitment, resulting in deformed sperm heads and male sterility. Loss of DOT1L results in transcriptional dysregulation coinciding with the onset of histone replacement and affecting genes required for histone-to-protamine exchange. DOT1L also deposits H3K79me2 and promotes accumulation of elongating RNA Polymerase II at the testis-specific bromodomain gene Brdt. Together, our results indicate that DOT1L is an important mediator of transcription during spermatid differentiation and an indispensable regulator of male fertility.
Topics: Animals; Male; Mice; Cell Differentiation; Chromatin Assembly and Disassembly; Histone-Lysine N-Methyltransferase; Histones; Protamines; Semen; Spermatids
PubMed: 37082969
DOI: 10.1242/dev.201497 -
Cell Death & Disease Nov 2016Male infertility due to abnormal spermatozoa has been reported in both animals and humans, but its pathogenic causes, including genetic abnormalities, remain largely... (Review)
Review
Male infertility due to abnormal spermatozoa has been reported in both animals and humans, but its pathogenic causes, including genetic abnormalities, remain largely unknown. On the other hand, contraceptive options for men are limited, and a specific, reversible and safe method of male contraception has been a long-standing quest in medicine. Some progress has recently been made in exploring the effects of spermatid-specifical genetic factors in controlling male fertility. A comprehensive search of PubMed for articles and reviews published in English before July 2016 was carried out using the search terms 'spermiogenesis failure', 'globozoospermia', 'spermatid-specific', 'acrosome', 'infertile', 'manchette', 'sperm connecting piece', 'sperm annulus', 'sperm ADAMs', 'flagellar abnormalities', 'sperm motility loss', 'sperm ion exchanger' and 'contraceptive targets'. Importantly, we have opted to focus on articles regarding spermatid-specific factors. Genetic studies to define the structure and physiology of sperm have shown that spermatozoa appear to be one of the most promising contraceptive targets. Here we summarize how these spermatid-specific factors regulate spermiogenesis and categorize them according to their localization and function from spermatid head to tail (e.g., acrosome, manchette, head-tail conjunction, annulus, principal piece of tail). In addition, we emphatically introduce small-molecule contraceptives, such as BRDT and PPP3CC/PPP3R2, which are currently being developed to target spermatogenic-specific proteins. We suggest that blocking the differentiation of haploid germ cells, which rarely affects early spermatogenic cell types and the testicular microenvironment, is a better choice than spermatogenic-specific proteins. The studies described here provide valuable information regarding the genetic and molecular defects causing male mouse infertility to improve our understanding of the importance of spermatid-specific factors in controlling fertility. Although a male contraceptive 'pill' is still many years away, research into the production of new small-molecule contraceptives targeting spermatid-specific proteins is the right avenue.
Topics: Contraceptive Agents; Endoplasmic Reticulum; Fertility; Humans; Male; Sperm Head; Sperm Tail; Spermatids
PubMed: 27831554
DOI: 10.1038/cddis.2016.344 -
Clinics (Sao Paulo, Brazil) 2013Intracytoplasmic injection with testicular spermatozoa has become a routine treatment in fertility clinics. Spermatozoa can be recovered in half of patients with... (Review)
Review
Intracytoplasmic injection with testicular spermatozoa has become a routine treatment in fertility clinics. Spermatozoa can be recovered in half of patients with nonobstructive azoospermia. The use of immature germ cells for intracytoplasmic injection has been proposed for cases in which no spermatozoa can be retrieved. However, there are low pregnancy rates following intracytoplasmic injection using round spermatids from men with no elongated spermatids or spermatozoa in their testes. The in vitro culture of immature germ cells to more mature stages has been proposed as a means to improve this poor outcome. Several years after the introduction of intracytoplasmic injection with elongating and round spermatids, uncertainty remains as to whether this approach can be considered a safe treatment option. This review outlines the clinical and scientific data regarding intracytoplasmic injection using immature germ cells and in vitro matured germ cells.
Topics: Female; Humans; Male; Oligospermia; Pregnancy; Sperm Injections, Intracytoplasmic; Sperm Maturation; Spermatids; Spermatogenesis
PubMed: 23503965
DOI: 10.6061/clinics/2013(sup01)17 -
Antioxidants & Redox Signaling Feb 2004Redox control of cell physiology is one of the most important regulatory mechanisms in all living organisms. The thioredoxin system, composed of thioredoxin and... (Review)
Review
Redox control of cell physiology is one of the most important regulatory mechanisms in all living organisms. The thioredoxin system, composed of thioredoxin and thioredoxin reductase, has emerged as a key player in cellular redox-mediated reactions. For many years, only one thioredoxin system had been described in higher organisms, ubiquitously expressed in the cytoplasm of eukaryotic cells. However, during the last decade, we and others have identified and characterized novel thioredoxin systems with unique properties, such as organelle-specific localization in mitochondria or endoplasmic reticulum, tissue-specific distribution mostly in the testis, and features novel for thioredoxins, such as microtubule-binding properties. In this review, we will focus on the mammalian testis-specific thioredoxin system that comprises three thioredoxins exclusively expressed in spermatids (named Sptrx-1, Sptrx-2, and Sptrx-3) and an additional thioredoxin highly expressed in testis, but also present in lung and other ciliated tissues (Txl-2). The implications of these findings in the context of male fertility and testicular cancer, as well as evolutionary aspects, will be discussed.
Topics: Animals; Humans; Male; Oxidation-Reduction; Phylogeny; Spermatids; Spermatozoa; Testis; Thioredoxin-Disulfide Reductase; Thioredoxins
PubMed: 14713334
DOI: 10.1089/152308604771978327