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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 -
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 -
Current Biology : CB Aug 2023The molecular mechanism underlying asymmetric axonemal complexes in sperm flagella is still largely unknown. Here, we showed that the knockout of the coiled-coil...
The molecular mechanism underlying asymmetric axonemal complexes in sperm flagella is still largely unknown. Here, we showed that the knockout of the coiled-coil domain-containing 176 (CCDC176) in mice led to male infertility due to decreased sperm motility. Ccdc176 knockout specifically destabilized microtubule doublets (MTDs) 1 and 9 during sperm maturation in the corpus epididymis. Single-sperm immunofluorescence showed that most CCDC176 was distributed along the axoneme, and further super-resolution imaging revealed that CCDC176 is asymmetrically localized in the sperm axoneme. CCDC176 could cooperate with microtubule and radial spoke proteins to stabilize MTDs 1 and 9, and its knockout results in the destabilization of some proteins in sperm flagella. Furthermore, as predicted by the sperm multibody dynamics (MBD) model, we found that MTDs 1 and 9 jutted out from the sperm flagellum annulus region in Ccdc176 spermatozoa, and these flagellar defects alter sperm flagellar beat patterns and swimming paths, potentially owing to the reduction and disequilibration of bending torque on the central pair. These results demonstrate that CCDC176 specifically stabilizes MTDs 1 and 9 in the sperm flagellum to ensure proper sperm movement for fertilization.
Topics: Male; Animals; Mice; Sperm Motility; Semen; Sperm Tail; Spermatozoa; Flagella; Microtubules; Axoneme
PubMed: 37494937
DOI: 10.1016/j.cub.2023.06.079 -
Frontiers in Bioscience (Scholar... Sep 2023Analysis of sperm morphology defects (amorphous heads, abnormal acrosome, etc.) is useful for estimating the efficiency of spermiogenesis and sperm maturation. An...
BACKGROUND
Analysis of sperm morphology defects (amorphous heads, abnormal acrosome, etc.) is useful for estimating the efficiency of spermiogenesis and sperm maturation. An advanced paternal age (more than 40 years) is associated with decreasing sperm count and reduced motility; however, there is little information on the effect of aging relating to sperm morphological defects. Moreover, searching for stable combinations of certain morphological defects in the same sperm can be useful for better understanding spermiogenesis. The aim of the study was to investigate age-related changes in sperm morphology and the prevalence of certain combinations of sperm morphological defects in men from the general population.
METHODS
Sperm morphology was assessed in 1266 volunteers from the Russian urban general population in different age groups (18-19, 20-24, 25-29, 30-34, 35-40, and over 40 years old). Two hundred sperm were evaluated from each semen sample (about 250 thousand spermatozoa in total). Sperm defects were classified according to the WHO laboratory manual (WHO, 2010). The total percentage of each sperm defect and the frequency of different combinations of sperm morphological anomalies for each age group were counted. Additionally, a similar analysis was performed for the groups of normospermia and pathozoospermia.
RESULTS
The frequency of coiled and short sperm tails increased in men over 40 years old compared to younger subjects; however, aging did not affect the percentage of morphologically normal sperm. It was shown that the combination of a misshaped head (amorphous, pyriform, and elongated) with a postacrosomal vacuole, acrosome defect, excess residual cytoplasm, or any anomaly of the midpiece or tail in the same spermatozoon were not random combinations of independent solitary defects. The increased frequency of combinations of coiled tails with amorphous, elongated, or vacuolated heads was observed in men older than 40 years. Sperm morphological defects, such as severely deformed heads (pyriform, elongated, and round) were more common in men with pathozoospermia compared to normospermic subjects.
CONCLUSIONS
An age-related impairment in sperm morphology was found. Stable combinations of head defects with anomalies in the acrosome, midpiece or tail suggest that these defects may be the result of a general violation in the morphogenetic mechanism.
Topics: Humans; Male; Adult; Semen; Spermatozoa; Acrosome; Sperm Tail; Semen Analysis
PubMed: 37806952
DOI: 10.31083/j.fbs1503012 -
Cells Aug 2023Osmoregulation plays a vital role in sperm function, encompassing spermatogenesis, maturation, and fertilization. Aquaglyceroporins, a subclass of aquaporins (AQPs),...
Osmoregulation plays a vital role in sperm function, encompassing spermatogenesis, maturation, and fertilization. Aquaglyceroporins, a subclass of aquaporins (AQPs), facilitate the transport of water and glycerol across the sperm membrane, with glycerol serving as an important substrate for sperm bioenergetics. This study aimed to elucidate the significance of AQP-mediated glycerol permeability in sperm motility. The presence and localization of AQP3 and AQP7 in human sperm were assessed using immunofluorescence. Subsequently, the glycerol permeability of spermatozoa obtained from normozoospermic individuals ( = 30) was measured, using stopped-flow light scattering, after incubation with specific aquaporin inhibitors targeting AQP3 (DFP00173), AQP7 (Z433927330), or general aquaglyceroporin (phloretin). Sperm from asthenozoospermic men ( = 30) were utilized to evaluate the AQP7-mediated glycerol permeability, and to compare it with that of normozoospermic men. Furthermore, hypermotile capacitated sperm cells were examined, to determine the AQP7 expression and membrane glycerol permeability. AQP3 was predominantly observed in the tail region, while AQP7 was present in the head, midpiece, and tail of human sperm. Our findings indicate that AQP7 plays a key role in glycerol permeability, as the inhibition of AQP7 resulted in a 55% decrease in glycerol diffusion across the sperm membrane. Importantly, this glycerol permeability impairment was evident in spermatozoa from asthenozoospermic individuals, suggesting the dysregulation of AQP7-mediated glycerol transport, despite similar AQP7 levels. Conversely, the AQP7 expression increased in capacitated sperm, compared to non-capacitated sperm. Hence, AQP7-mediated permeability may serve as a valuable indicator of sperm motility, and be crucial in sperm function.
Topics: Humans; Male; Aquaglyceroporins; Aquaporins; Asthenozoospermia; Glycerol; Permeability; Semen; Sperm Capacitation; Sperm Motility
PubMed: 37566082
DOI: 10.3390/cells12152003 -
Conservation Physiology 2023Managing a species of conservation concern can be best achieved when there is information on the reproductive physiology of both sexes available; however, many species...
Managing a species of conservation concern can be best achieved when there is information on the reproductive physiology of both sexes available; however, many species lack this critical, baseline information. One such species, the tuatara (), is the last surviving member of one of the four reptile orders (Rhynchocephalia) and is the only reptile known to lack a male intromittent organ. Culturally and evolutionarily significant, the conservation of this species is a global priority for the maintenance of biodiversity. In light of this, we characterized the morphology, viability and swim speed of mature tuatara sperm for the first time. We found that tuatara sperm are filiform and bear the remarkably conserved three-part sperm structure seen across the animal kingdom. Tuatara sperm are long (mean total length 166 μm), with an approximate head:midpiece:tail ratio of 15:1:17. While tuatara sperm are capable of high levels of within-mating viability (94.53%), the mean viability across all samples was 58.80%. Finally, tuatara sperm had a mean curvilinear velocity swim speed (μ × s - 1) of 82.28. At the population level, there were no differences in viability or mean swim speed between sperm collected from a male's first mating of a season and repeat matings; however, the maximum sperm swim speed increased in observed repeated matings relative to first matings. Interestingly, faster sperm samples had shorter midpieces, but had greater viability and longer head and tail sections. This work expands our understanding of male reproductive characteristics and their variation to a new order, provides wild references for the assessment of captive individuals, lays the groundwork for potential assisted reproductive techniques and highlights variation in male reproductive potential as an important factor for consideration in future conservation programs for this unique species.
PubMed: 37663926
DOI: 10.1093/conphys/coad071 -
Journal of Cellular and Molecular... Apr 2024Oligoasthenoteratospermia (OAT), characterized by abnormally low sperm count, poor sperm motility, and abnormally high number of deformed spermatozoa, is an important...
Oligoasthenoteratospermia (OAT), characterized by abnormally low sperm count, poor sperm motility, and abnormally high number of deformed spermatozoa, is an important cause of male infertility. Its genetic basis in many affected individuals remains unknown. Here, we found that CCDC157 variants are associated with OAT. In two cohorts, a 21-bp (g.30768132_30768152del21) and/or 24-bp (g.30772543_30772566del24) deletion of CCDC157 were identified in five sporadic OAT patients, and 2 cases within one pedigree. In a mouse model, loss of Ccdc157 led to male sterility with OAT-like phenotypes. Electron microscopy revealed misstructured acrosome and abnormal head-tail coupling apparatus in the sperm of Ccdc157-null mice. Comparative transcriptome analysis showed that the Ccdc157 mutation alters the expressions of genes involved in cell migration/motility and Golgi components. Abnormal Golgi apparatus and decreased expressions of genes involved in acrosome formation and lipid metabolism were detected in Ccdc157-deprived mouse germ cells. Interestingly, we attempted to treat infertile patients and Ccdc157 mutant mice with a Chinese medicine, Huangjin Zanyu, which improved the fertility in one patient and most mice that carried the heterozygous mutation in CCDC157. Healthy offspring were produced. Our study reveals CCDC157 is essential for sperm maturation and may serve as a marker for diagnosis of OAT.
Topics: Animals; Humans; Male; Mice; Asthenozoospermia; Infertility, Male; Mice, Knockout; Mutation; Oligospermia; Semen; Sperm Motility; Spermatozoa; Membrane Proteins
PubMed: 38509755
DOI: 10.1111/jcmm.18215 -
Animals : An Open Access Journal From... Jul 2023Sperm morphology can predict the reproductive male fertilizing potential. This study aimed to determine the morphological and morphometric spermatozoa characteristics...
Sperm morphology can predict the reproductive male fertilizing potential. This study aimed to determine the morphological and morphometric spermatozoa characteristics from guinea pigs subjected to different photoperiodic stimulation. Thirty F1 guinea pigs were randomly assigned to three photoperiodic treatments: FT1 (photoperiod with 10 Light/14 Dark LED light), FT2 (photoperiod with 10L/14D sunlight), and FT0 (room without direct light source). At 107 ± 9.8 days of age, sperm concentration and motility were higher in the FT0 and FT1 groups ( < 0.05); furthermore, there were no differences in nucleus length and ellipticity between the FT0 and FT1 groups, but the sperm of the FT1 group was higher in perimeter and nuclear area, while that of the FT0 group was higher in roughness, regularity, midpiece length, and tail ( < 0.01). Expanding acrosome (Type 2) was more frequent in the FT2 group, but there was variation in head measurements between all morphological categories. Pregnancy rate, calving age, and mating age were higher in the FT0 group; meanwhile, the FT1 group initiated successful matings earlier ( < 0.01). The FT0 group had a higher fertility rate, and the age of mating and first calving were earlier in the FT1 group than the FT0 group, but no pregnancies were reported for the FT2 group. Photoperiodic stimulation can increase the morphometric dimensions of guinea pig spermatozoa, favoring the reproductive characteristics, but sunlight could reduce their size due to heat stress.
PubMed: 37508028
DOI: 10.3390/ani13142249 -
Cellular and Molecular Life Sciences :... Dec 2023Multiple morphological abnormalities of the flagella (MMAF) is a severe disease of male infertility, while the pathogenetic mechanisms of MMAF are still incompletely...
Multiple morphological abnormalities of the flagella (MMAF) is a severe disease of male infertility, while the pathogenetic mechanisms of MMAF are still incompletely understood. Previously, we found that the deficiency of Ccdc38 might be associated with MMAF. To understand the underlying mechanism of this disease, we identified the potential partner of this protein and found that the coiled-coil domain containing 146 (CCDC146) can interact with CCDC38. It is predominantly expressed in the testes, and the knockout of this gene resulted in complete infertility in male mice but not in females. The knockout of Ccdc146 impaired spermiogenesis, mainly due to flagellum and manchette organization defects, finally led to MMAF-like phenotype. Furthermore, we demonstrated that CCDC146 could interact with both CCDC38 and CCDC42. It also interacts with intraflagellar transport (IFT) complexes IFT88 and IFT20. The knockout of this gene led to the decrease of ODF2, IFT88, and IFT20 protein levels, but did not affect CCDC38, CCDC42, or ODF1 expression. Additionally, we predicted and validated the detailed interactions between CCDC146 and CCDC38 or CCDC42, and built the interaction models at the atomic level. Our results suggest that the testis predominantly expressed gene Ccdc146 is essential for sperm flagellum biogenesis and male fertility, and its mutations might be associated with MMAF in some patients.
Topics: Animals; Male; Mice; Fertility; Heat-Shock Proteins; Infertility, Male; Mice, Knockout; Semen; Sperm Tail; Spermatozoa; Testis; Microtubule-Associated Proteins
PubMed: 38038747
DOI: 10.1007/s00018-023-05025-x