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Human Reproduction Update Feb 2022Autophagy is an intracellular catabolic process of degrading and recycling proteins and organelles to modulate various physiological and pathological events, including... (Review)
Review
BACKGROUND
Autophagy is an intracellular catabolic process of degrading and recycling proteins and organelles to modulate various physiological and pathological events, including cell differentiation and development. Emerging data indicate that autophagy is closely associated with male reproduction, especially the biosynthetic and catabolic processes of sperm. Throughout the fate of sperm, a series of highly specialized cellular events occur, involving pre-testicular, testicular and post-testicular events. Nonetheless, the most fundamental question of whether autophagy plays a protective or harmful role in male reproduction, especially in sperm, remains unclear.
OBJECTIVE AND RATIONALE
We summarize the functional roles of autophagy in the pre-testicular (hypothalamic-pituitary-testis (HPG) axis), testicular (spermatocytogenesis, spermatidogenesis, spermiogenesis, spermiation) and post-testicular (sperm maturation and fertilization) processes according to the timeline of sperm fate. Additionally, critical mechanisms of the action and clinical impacts of autophagy on sperm are identified, laying the foundation for the treatment of male infertility.
SEARCH METHODS
In this narrative review, the PubMed database was used to search peer-reviewed publications for summarizing the functional roles of autophagy in the fate of sperm using the following terms: 'autophagy', 'sperm', 'hypothalamic-pituitary-testis axis', 'spermatogenesis', 'spermatocytogenesis', 'spermatidogenesis', 'spermiogenesis', 'spermiation', 'sperm maturation', 'fertilization', 'capacitation' and 'acrosome' in combination with autophagy-related proteins. We also performed a bibliographic search for the clinical impact of the autophagy process using the keywords of autophagy inhibitors such as 'bafilomycin A1', 'chloroquine', 'hydroxychloroquine', '3-Methyl Adenine (3-MA)', 'lucanthone', 'wortmannin' and autophagy activators such as 'rapamycin', 'perifosine', 'metformin' in combination with 'disease', 'treatment', 'therapy', 'male infertility' and equivalent terms. In addition, reference lists of primary and review articles were reviewed for additional relevant publications. All relevant publications until August 2021 were critically evaluated and discussed on the basis of relevance, quality and timelines.
OUTCOMES
(i) In pre-testicular processes, autophagy-related genes are involved in the regulation of the HPG axis; and (ii) in testicular processes, mTORC1, the main gate to autophagy, is crucial for spermatogonia stem cell (SCCs) proliferation, differentiation, meiotic progression, inactivation of sex chromosomes and spermiogenesis. During spermatidogenesis, autophagy maintains haploid round spermatid chromatoid body homeostasis for differentiation. During spermiogenesis, autophagy participates in acrosome biogenesis, flagella assembly, head shaping and the removal of cytoplasm from elongating spermatid. After spermatogenesis, through PDLIM1, autophagy orchestrates apical ectoplasmic specialization and basal ectoplasmic specialization to handle cytoskeleton assembly, governing spermatid movement and release during spermiation. In post-testicular processes, there is no direct evidence that autophagy participates in the process of capacitation. However, autophagy modulates the acrosome reaction, paternal mitochondria elimination and clearance of membranous organelles during fertilization.
WIDER IMPLICATIONS
Deciphering the roles of autophagy in the entire fate of sperm will provide valuable insights into therapies for diseases, especially male infertility.
Topics: Autophagy; Humans; Infertility, Male; Male; Spermatids; Spermatogenesis; Spermatozoa
PubMed: 34967891
DOI: 10.1093/humupd/dmab043 -
Cell Reports Nov 2018Spermatogenesis is a complex and dynamic cellular differentiation process critical to male reproduction and sustained by spermatogonial stem cells (SSCs). Although...
Spermatogenesis is a complex and dynamic cellular differentiation process critical to male reproduction and sustained by spermatogonial stem cells (SSCs). Although patterns of gene expression have been described for aggregates of certain spermatogenic cell types, the full continuum of gene expression patterns underlying ongoing spermatogenesis in steady state was previously unclear. Here, we catalog single-cell transcriptomes for >62,000 individual spermatogenic cells from immature (postnatal day 6) and adult male mice and adult men. This allowed us to resolve SSC and progenitor spermatogonia, elucidate the full range of gene expression changes during male meiosis and spermiogenesis, and derive unique gene expression signatures for multiple mouse and human spermatogenic cell types and/or subtypes. These transcriptome datasets provide an information-rich resource for studies of SSCs, male meiosis, testicular cancer, male infertility, or contraceptive development, as well as a gene expression roadmap to be emulated in efforts to achieve spermatogenesis in vitro.
Topics: Adult; Aging; Animals; Cell Differentiation; Gene Expression Regulation, Developmental; Haploidy; Humans; Male; Mammals; Meiosis; Mice, Inbred C57BL; Signal Transduction; Single-Cell Analysis; Spermatids; Spermatogenesis; Spermatogonia; Stem Cells; Testis; Transcriptome
PubMed: 30404016
DOI: 10.1016/j.celrep.2018.10.026 -
Seminars in Cell & Developmental Biology Sep 2018It is conceivable that spermatid apico-basal polarity and spermatid planar cell polarity (PCP) are utmost important to support spermatogenesis. The orderly arrangement... (Review)
Review
It is conceivable that spermatid apico-basal polarity and spermatid planar cell polarity (PCP) are utmost important to support spermatogenesis. The orderly arrangement of developing germ cells in particular spermatids during spermiogenesis are essential to obtain structural and nutrient supports from the fixed number of Sertoli cells across the limited space of seminiferous epithelium in the tubules following Sertoli cell differentiation by ∼17 day postpartum (dpp) in rodents and ∼12 years of age at puberty in humans. Yet few studies are found in the literature to investigate the role of these proteins to support spermatogenesis. Herein, we briefly summarize recent findings in the field, in particular emerging evidence that supports the concept that apico-basal polarity and PCP are conferred by the corresponding polarity proteins through their effects on the actin- and microtubule (MT)-based cytoskeletons. While much research is needed to bridge our gaps of understanding cell polarity, cytoskeletal function, and signaling proteins, a critical evaluation of some latest findings as summarized herein provides some important and also thought-provoking concepts to design better functional experiments to address this important, yet largely expored, research topic.
Topics: Actins; Animals; Cell Polarity; Cytoskeleton; Humans; Male; Microtubules; Sertoli Cells; Spermatids; Testis
PubMed: 29410206
DOI: 10.1016/j.semcdb.2018.01.013 -
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 -
Seminars in Cell & Developmental Biology Jun 2014The transport of germ cells across the seminiferous epithelium is composed of a series of cellular events during the epithelial cycle essential to the completion of... (Review)
Review
The transport of germ cells across the seminiferous epithelium is composed of a series of cellular events during the epithelial cycle essential to the completion of spermatogenesis. Without the timely transport of spermatids during spermiogenesis, spermatozoa that are transformed from step 19 spermatids in the rat testis fail to reach the luminal edge of the apical compartment and enter the tubule lumen at spermiation, thereby arriving the epididymis for further maturation. Step 19 spermatids and/or sperms that remain in the epithelium beyond stage VIII of the epithelial cycle will be removed by the Sertoli cell via phagocytosis to form phagosomes and be degraded by lysosomes, leading to subfertility and/or infertility. However, the biology of spermatid transport, in particular the final events that lead to spermiation remain elusive. Based on recent data in the field, we critically evaluate the biology of spermiation herein by focusing on the actin binding proteins (ABPs) that regulate the organization of actin microfilaments at the Sertoli-spermatid interface, which is crucial for spermatid transport during this event. The hypothesis we put forth herein also highlights some specific areas of research that can be pursued by investigators in the years to come.
Topics: Actins; Animals; Humans; Male; Microfilament Proteins; Protein Multimerization; Signal Transduction; Sperm Transport; Spermatids
PubMed: 24735648
DOI: 10.1016/j.semcdb.2014.04.018 -
Genes Apr 2021Nuclear architecture undergoes an extensive remodeling during spermatogenesis, especially at levels of spermatocytes (SPC) and spermatids (SPT). Interestingly, typical... (Review)
Review
Nuclear architecture undergoes an extensive remodeling during spermatogenesis, especially at levels of spermatocytes (SPC) and spermatids (SPT). Interestingly, typical events of spermiogenesis, such as nuclear elongation, acrosome biogenesis, and flagellum formation, need a functional cooperation between proteins of the nuclear envelope and acroplaxome/manchette structures. In addition, nuclear envelope plays a key role in chromosome distribution. In this scenario, special attention has been focused on the LINC (linker of nucleoskeleton and cytoskeleton) complex, a nuclear envelope-bridge structure involved in the connection of the nucleoskeleton to the cytoskeleton, governing mechanotransduction. It includes two integral proteins: KASH- and SUN-domain proteins, on the outer (ONM) and inner (INM) nuclear membrane, respectively. The LINC complex is involved in several functions fundamental to the correct development of sperm cells such as head formation and head to tail connection, and, therefore, it seems to be important in determining male fertility. This review provides a global overview of the main LINC complex components, with a special attention to their subcellular localization in sperm cells, their roles in the regulation of sperm morphological maturation, and, lastly, LINC complex alterations associated to male infertility.
Topics: Animals; Cell Nucleus; Cytoskeleton; Humans; Infertility, Male; Male; Mechanotransduction, Cellular; Nuclear Envelope; Nuclear Matrix; Spermatids; Spermatocytes; Spermatozoa
PubMed: 33925685
DOI: 10.3390/genes12050658 -
Cell Stem Cell Mar 2016In vitro generation of functional gametes is a promising approach for treating infertility, although faithful replication of meiosis has proven to be a substantial...
In vitro generation of functional gametes is a promising approach for treating infertility, although faithful replication of meiosis has proven to be a substantial obstacle to deriving haploid gamete cells in culture. Here we report complete in vitro meiosis from embryonic stem cell (ESC)-derived primordial germ cells (PGCLCs). Co-culture of PGCLCs with neonatal testicular somatic cells and sequential exposure to morphogens and sex hormones reproduced key hallmarks of meiosis, including erasure of genetic imprinting, chromosomal synapsis and recombination, and correct nuclear DNA and chromosomal content in the resulting haploid cells. Intracytoplasmic injection of the resulting spermatid-like cells into oocytes produced viable and fertile offspring, showing that this robust stepwise approach can functionally recapitulate male gametogenesis in vitro. These findings provide a platform for investigating meiotic mechanisms and the potential generation of human haploid spermatids in vitro.
Topics: Animals; Chromosomes, Mammalian; Coculture Techniques; Humans; Male; Meiosis; Mice; Mice, Transgenic; Mouse Embryonic Stem Cells; Spermatids; Spermatogenesis
PubMed: 26923202
DOI: 10.1016/j.stem.2016.01.017 -
Biochimica Et Biophysica Acta Mar 2014The function of sperm is to safely transport the haploid paternal genome to the egg containing the maternal genome. The subsequent fertilization leads to transmission of... (Review)
Review
The function of sperm is to safely transport the haploid paternal genome to the egg containing the maternal genome. The subsequent fertilization leads to transmission of a new unique diploid genome to the next generation. Before the sperm can set out on its adventurous journey, remarkable arrangements need to be made during the post-meiotic stages of spermatogenesis. Haploid spermatids undergo extensive morphological changes, including a striking reorganization and compaction of their chromatin. Thereby, the nucleosomal, histone-based structure is nearly completely substituted by a protamine-based structure. This replacement is likely facilitated by incorporation of histone variants, post-translational histone modifications, chromatin-remodeling complexes, as well as transient DNA strand breaks. The consequences of mutations have revealed that a protamine-based chromatin is essential for fertility in mice but not in Drosophila. Nevertheless, loss of protamines in Drosophila increases the sensitivity to X-rays and thus supports the hypothesis that protamines are necessary to protect the paternal genome. Pharmaceutical approaches have provided the first mechanistic insights and have shown that hyperacetylation of histones just before their displacement is vital for progress in chromatin reorganization but is clearly not the sole inducer. In this review, we highlight the current knowledge on post-meiotic chromatin reorganization and reveal for the first time intriguing parallels in this process in Drosophila and mammals. We conclude with a model that illustrates the possible mechanisms that lead from a histone-based chromatin to a mainly protamine-based structure during spermatid differentiation. This article is part of a Special Issue entitled: Chromatin and epigenetic regulation of animal development.
Topics: Animals; Chromatin Assembly and Disassembly; DNA Breaks; Drosophila melanogaster; Genomic Instability; Histones; Humans; Male; Mice; Nucleosomes; Protein Processing, Post-Translational; Spermatids; Spermatogenesis
PubMed: 24091090
DOI: 10.1016/j.bbagrm.2013.08.004 -
Cells Feb 2022Post-transcriptional and translational control of specialized genes play a critical role in the progression of spermatogenesis. During the early stages, mRNAs are... (Review)
Review
Post-transcriptional and translational control of specialized genes play a critical role in the progression of spermatogenesis. During the early stages, mRNAs are actively transcribed and stored, temporarily bound to RNA binding proteins in chromatoid bodies (CBs). CBs are membrane-less dynamic organelles which serve as storehouses and processing centers of mRNAs awaiting translation during later stages of spermatogenesis. These CBs can also regulate the stability of mRNAs to secure the correct timing of protein expression at different stages of sperm formation. Gonadotropin-regulated testicular RNA helicase (GRTH/DDX25) is an essential regulator of spermatogenesis. GRTH transports mRNAs from the nucleus to the cytoplasm and phospho-GRTH transports mRNAs from the cytoplasm to the CBs. During spermiogenesis, there is precise control of mRNAs transported by GRTH from and to the CBs, directing the timing of translation of critical proteins which are involved in spermatid elongation and acrosomal development, resulting in functional sperm formation. This chapter presents our current knowledge on the role of GRTH, phospho-GRTH and CBs in the control of spermiogenesis. In addition, it covers the components of CBs compared to those of stress granules and P-bodies.
Topics: DEAD-box RNA Helicases; Germ Cell Ribonucleoprotein Granules; Humans; Male; RNA, Messenger; RNA-Binding Proteins; Spermatids; Spermatogenesis
PubMed: 35203264
DOI: 10.3390/cells11040613 -
Reproductive Biology and Endocrinology... Apr 2012Tubulobulbar complexes (TBCs) are actin-based structures that help establish close contact between Sertoli-Sertoli cells or Sertoli-mature germ cells (spermatids) in the... (Review)
Review
Tubulobulbar complexes (TBCs) are actin-based structures that help establish close contact between Sertoli-Sertoli cells or Sertoli-mature germ cells (spermatids) in the seminiferous tubules of the testes. They are actin-rich push-through devices that eliminate excess spermatid cytoplasm and prepare mature spermatids for release into the tubular lumen. Just prior to spermiation, the elongated spermatid interacts with the Sertoli cell via an extensive structure comprising various adhesion molecules called the apical ectoplasmic specialization which is partially replaced by the apical TBC, on the concave surface of the spermatid head. The sperm release process involves extensive restructuring, namely the disassembly and reassembly of junctions at the Sertoli-spermatid interface in the seminiferous epithelium. Based on the presence of different classes of molecules in the TBCs or the defects observed in the absence of TBCs, the main functions attributed to TBCs are elimination of excess spermatid cytoplasm, endocytosis and recycling of junctional molecules, shaping of the spermatid acrosome, and forming transient anchoring devices for mature spermatids before they are released. This review summarizes the recent findings that focus on the role of TBCs in cell cytoskeleton restructuring during sperm release in the testes and the molecular mechanism involved.
Topics: Actins; Adaptor Proteins, Signal Transducing; Adherens Junctions; Animals; Endocytosis; Humans; Male; Microtubules; Rats; Seminiferous Epithelium; Seminiferous Tubules; Sertoli Cells; Spermatids; Spermatogenesis; Spermatozoa
PubMed: 22510523
DOI: 10.1186/1477-7827-10-27