Molecular human reproduction最新文献

{"title":"Human platelet-rich plasma promotes primordial follicle activation via the PI3K/Akt signaling pathway.","authors":"Yashuang Weng, Wenbo Zhang, Fan Qu, Zehua Deng, Xiaodan Zhang, Shuang Liu, Hongwei Wei, Tiantian Hao, Longwei Gao, Meijia Zhang, Yuezhou Chen","doi":"10.1093/molehr/gaaf007","DOIUrl":"10.1093/molehr/gaaf007","url":null,"abstract":"<p><p>The activation of dormant primordial follicles is a promising method to improve the fertility of premature ovarian insufficiency (POI) patients. Many experiments from both human and animal studies suggest that human platelet-rich plasma (hPRP) may restore ovarian function and promote follicle growth. However, the underlying mechanisms remain unclear. In the current study, our results demonstrate that hPRP significantly increased the number of growing follicles and promoted the proliferation of granulosa cells in cultured mouse ovaries. hPRP also significantly increased the protein levels of phosphorylated protein kinase B (p-Akt) and forkhead box O3a (p-FOXO3a), as well as the number of oocytes with FOXO3a nuclear export in cultured mouse ovaries. Immunofluorescence results showed that in vitro treatment with hPRP significantly increased the fluorescence intensity of p-Akt in oocytes. The inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway by LY294002 blocked the hPRP-induced increase in the number of growing follicles in cultured mouse ovaries. Furthermore, hPRP injected i.p. or added to the medium significantly increased the number of growing follicles and the protein levels of p-Akt in the ovaries of newborn mice and in cultured human ovarian tissues. Taken together, our findings from mouse and human experiments indicate that hPRP promotes the activation of primordial follicles through the PI3K/Akt signaling pathway in oocytes.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein-targeting reverse genetic approaches: the future of oocyte and preimplantation embryo research.","authors":"Nicole J Camlin","doi":"10.1093/molehr/gaaf008","DOIUrl":"https://doi.org/10.1093/molehr/gaaf008","url":null,"abstract":"<p><p>Reverse genetic approaches are the standard in molecular biology to determine a protein's function. Traditionally, nucleic acid targeting via gene knockout (DNA) and knockdown (RNA) has been the method of choice to remove proteins-of-interest. However, the nature of mammalian oocyte maturation and preimplantation embryo development can make nucleic acid targeting approaches difficult. Gene knockout allows time for compensatory mechanisms and secondary phenotypes to develop which can make interpretation of a protein's function difficult. Furthermore, genes can be essential for animal and/or oocyte survival, and therefore, gene knockout is not always a viable approach to investigate oocyte maturation and preimplantation embryo development. Conversely, RNA-targeting approaches, ie RNA interference (RNAi) and morpholinos, rely on protein half-life and therefore are unable to knockdown every protein-of-interest. An increasing number of reverse genetic approaches that directly target proteins have been developed to overcome the limitations of nucleic acid-based approaches, including Trim-Away and auxin-inducible degradation. These protein-targeting approaches give researchers exquisite and fast control of protein loss. This review will discuss how Trim-Away and auxin-inducible degradation can overcome many of the challenges of nucleic acid based reverse genetic approaches. Furthermore, it highlights the unique research opportunities these approaches afford, such as targeting post-translationally modified proteins.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MCP-1 promotes ILK phosphorylation at Ser246 during endometriosis development and affects the pregnancy outcome.","authors":"Upendra Kumar Soni, Rupal Tripathi, Pushplata Sankhwar, Suparna Kumari, Mohini Soni, Anveshika Manoj, Vaibhave Ubba, Satish Gupta, Raj Kumar Verma, J Venkatesh Pratap, Rajesh Kumar Jha","doi":"10.1093/molehr/gaaf004","DOIUrl":"https://doi.org/10.1093/molehr/gaaf004","url":null,"abstract":"<p><p>In women with endometriosis, monocyte chemoattractant protein 1 (MCP-1) or chemokine (C-C motif) ligand 2 (CCL2) is elevated in serum, peritoneal fluid, and endometriotic lesions, though its exact role in endometriosis is still unknown. The MCP-1 downstream molecule integrin-linked kinase (ILK) is involved in several cellular events. Our recent findings suggest that MCP-1 promotes an inflammatory response via ILK in a mouse endometriosis model. MCP-1 also favors human endometriotic cell aggregation, colonization, migration, and invasion, which are reversed by the ILK inhibitor compound (CPD) 22 (600 nM). Furthermore, the inflammatory response to MCP-1 is reduced by ILK inhibition (CPD22, 20 mg/kg body weight) in a mouse model. We studied MCP-1/chemokine (C-C motif) receptor type (CCR)2-mediated ILK signaling in endometriosis and observe a positive association of ILK and CCR2 with endometriosis in patients. Our immunoprecipitation and molecular docking studies confirm ILK interaction with CCR2 under a high MCP-1 level in Hs832(C).TCs (human endometriotic cells). MCP-1 promotes ILK-Ser246 phosphorylation in endometriotic cells in human and mouse models. The mouse model shows the same inflammatory markers as seen in human endometriosis and mimics some of the aspects of the inflammatory reaction. Targeting ILK by CDP22 (20 mg/kg) suppresses endometriosis progression in the mouse model. Altered MCP-1-ILK signaling leads to poor pregnancy outcomes in the mouse model. Further, the in-silico results suggest that CPD22 stabilizes the interaction with Asp234 and His318 residues of ILK and inhibits the Ser246 phosphorylation. In conclusion, MCP-1 activates ILK at the S246 residue and leads to lesion development/progression, reflecting the therapeutic importance of ILK for endometriosis management through the mouse model.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An aberrant protamine ratio is associated with decreased H4ac levels in murine and human sperm.","authors":"Alexander Kruse, Simon Schneider, Gina Esther Merges, Andreas Christian Fröbius, Ignasi Forné, Axel Imhof, Hubert Schorle, Klaus Steger","doi":"10.1093/molehr/gaaf003","DOIUrl":"10.1093/molehr/gaaf003","url":null,"abstract":"<p><p>Protamine 2 (Prm2/PRM2), together with Protamine 1 (Prm1/PRM1), constitute the two protamines found in both murine and human sperm. During spermiogenesis in haploid male germ cells, chromatin undergoes significant condensation, a phase in which most histones are replaced by a species-specific ratio of these two protamines. Altered PRM1/PRM2 ratios are associated with subfertility and infertility in both male mice and men. Notably, during histone-to-protamine exchange, a small fraction of histones remains (ranging from 1% to 15%) bound to DNA. The regulatory roles of these residual histones, governed by post-translational modifications (PTMs), play a pivotal role in spermatogenesis, particularly in chromatin remodelling and epigenetic regulation of genes during sperm differentiation or even in early embryogenesis. In this study, utilizing a Prm2-deficient mouse model and conducting an analysis of sperm samples from men exhibiting either normozoospermia or atypical spermiograms, we observed alterations in the methylation and acetylation profiles of histones H3 and H4. Subsequent in-depth analysis revealed that discrepancies in protamine ratios do not significantly influence the PTMs of histones in testicular sperm. In murine epididymal sperm, altered protamine ratios are associated with reduced acetylation of histone H4 (H4ac), a phenomenon similarly observed in ejaculated sperm from men. In particular, H4K5ac and H4K12ac were identified as the two modifications that appear to decrease as a result of reduced Prm2/PRM2 levels. Our findings reveal that Protamine 2 is necessary for the maintenance of specific histone PTMs, such as acetylation, which is essential for proper spermatogenesis and particularly for chromatin remodelling.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143502570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mouse modeling of familial human SYCE1 c.197-2A>G splice site mutation leads to meiotic recombination failure and non-obstructive azoospermia.","authors":"Omar Ignacio García-Martínez, Adriana Geisinger, Eliana de Los Santos, Federico F Santiñaque, Gustavo A Folle, Jorge Luis Pórfido, María Noel Meikle, Geraldine Schlapp, Martina Crispo, Ricardo Benavente, Rosana Rodríguez-Casuriaga","doi":"10.1093/molehr/gaaf002","DOIUrl":"10.1093/molehr/gaaf002","url":null,"abstract":"<p><p>Infertility affects a considerable number of couples at reproductive age, with an incidence of 10-15%. Approximately 25% of cases are classified as idiopathic infertility. Often, errors during the meiotic stage appear to be related to idiopathic infertility. A crucial component during the first meiotic prophase is the synaptonemal complex (SC), which plays a fundamental role in homologous chromosome pairing and meiotic recombination. In many studies with infertile patients, mutations affecting SC-coding genes have been identified. The generation of humanized models has high physiological relevance, helping to clarify the molecular bases of pathology, which in turn is essential for the development of therapeutic procedures. Here, we report the generation and characterization of genetically modified mice carrying a mutation equivalent to SYCE1 c.197-2A>G, previously found in male infertile patients, aiming to determine the actual effects of this mutation on reproductive capacity and to study the underlying molecular mechanisms. Homozygous mutants were infertile. SYCE1 protein was not detected and Syce1 transcript presented minimal levels, suggesting transcript degradation underlying the infertility mechanism. Additionally, homozygous mutants showed impaired homologous chromosome synapsis, meiotic arrest before the pachytene stage, and increased apoptosis of meiotic cells. This study validates the variant as pathogenic and causative of infertility, since the observed dramatic phenotype was attributable to this single homozygous point mutation, when compared to WT and heterozygous littermates. Moreover, although this homozygous point mutation has been only found in infertile men thus far, we anticipate that if it were present in women, it would cause infertility as well, as homozygous female mice also exhibited an infertility phenotype.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioenergetics of human spermatozoa in patients with testicular germ cell tumours.","authors":"Ondrej Simonik, Barbora Bryndova, Vishma Pratap Sur, Lukas Ded, Zuzana Cockova, Ales Benda, Maryam Qasemi, Petr Pecina, Alena Pecinova, Daniela Spevakova, Tomas Hradec, Pavel Skrobanek, Zuzana Ezrova, Zuzana Kratka, Radomir Kren, Michal Jeseta, Ludmila Boublikova, Libor Zamecnik, Tomas Büchler, Jiri Neuzil, Pavla Postlerova, Katerina Komrskova","doi":"10.1093/molehr/gaaf005","DOIUrl":"10.1093/molehr/gaaf005","url":null,"abstract":"<p><p>In patients with testicular germ cell tumours (TGCT), sperm cryopreservation prior to anti-cancer treatment represents the main fertility preservation approach. However, it is associated with a low sperm recovery rate after thawing. Since sperm is a high-energy demanding cell, which is supplied by glycolysis and oxidative phosphorylation (OXPHOS), mitochondrial dysfunctionality can directly result in sperm anomalies. In this study, we investigated the bioenergetic pattern of cryopreserved sperm of TGCT patients in comparison with normozoospermic samples using two state-of-the-art methods: the Extracellular Flux Analyzer (XF Analyzer) and two-photon fluorescence lifetime imaging microscopy (2P-FLIM), in order to assess the contributions of OXPHOS and glycolysis to energy provision. A novel protocol for the combined measurement of OXPHOS (oxygen consumption rate: OCR) and glycolysis (extracellular acidification rate: ECAR) using the XF Analyzer was developed together with a unique customized AI-based approach for semiautomated processing of 2P-FLIM images. Our study delivers optimized low-HEPES modified human tubal fluid media (mHTF) for sperm handling during pre-analytical and analytical phases, to maintain sperm physiological parameters and optimal OCR, equivalent to OXPHOS. The negative effect of cryopreservation was signified by the deterioration of both bioenergetic pathways represented by modified OCR and ECAR curves and the derived parameters. This was true for normozoospermic as well as samples from TGCT patients, which showed even stronger damage within the respiratory chain compared to the level of glycolytic activity impairment. The impact of cryopreservation and pathology are supported by 2P-FLIM analysis, showing a significant decrease in bound NADH in contrast to unbound NAD(P)H, which reflects decreased metabolic activity in samples from TGCT patients. Our study provides novel insights into the impact of TGCT on sperm bioenergetics and delivers a verified protocol to be used for the assessment of human sperm metabolic activity, which can be a valuable tool for further research and clinical andrology.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143575909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Animal and vegetal materials of mouse oocytes segregate at first zygotic cleavage: a simple mechanism that makes the two-cell blastomeres differ reciprocally from the start.","authors":"Thomas Nolte, Reza Halabian, Steffen Israel, Yutaka Suzuki, Roberto A Avelar, Daniel Palmer, Georg Fuellen, Wojciech Makalowski, Michele Boiani","doi":"10.1093/molehr/gaae045","DOIUrl":"10.1093/molehr/gaae045","url":null,"abstract":"<p><p>Recent advances in embryology have shown that the sister blastomeres of two-cell mouse and human embryos differ reciprocally in potency. An open question is whether the blastomeres became different as opposed to originating as different. Here we wanted to test two relevant but conflicting models: one proposing that each blastomere contains both animal and vegetal materials in balanced proportions because the plane of first cleavage runs close to the animal-vegetal axis of the fertilized oocyte (meridional cleavage); and the other model proposing that each blastomere contains variable proportions of animal and vegetal materials because the plane of the first cleavage can vary - up to an equatorial orientation - depending on the topology of fertilization. Therefore, we imposed the fertilization site in three distinct regions of mouse oocytes (animal pole, vegetal pole, equator) via ICSI. After the first zygotic cleavage, the sister blastomeres were dissociated and subjected to single-cell transcriptome analysis, keeping track of the original pair associations. Non-supervised hierarchical clustering revealed that the frequency of correct pair matches varied with the fertilization site (vegetal pole > animal pole > equator), thereby, challenging the first model of balanced partitioning. However, the inter-blastomere differences had similar signatures of gene ontology across the three groups, thereby, also challenging the competing model of variable partitioning. These conflicting observations could be reconciled if animal and vegetal materials were partitioned at the first cleavage: an event considered improbable and possibly deleterious in mammals. We tested this occurrence by keeping the fertilized oocytes immobilized from the time of ICSI until the first cleavage. Image analysis revealed that cleavage took place preferentially along the short (i.e. equatorial) diameter of the oocyte, thereby partitioning the animal and vegetal materials into the two-cell blastomeres. Our results point to a simple mechanism by which the two sister blastomeres start out as different, rather than becoming different.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11741683/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endometrial stromal cell signaling and microRNA exosome content in women with adenomyosis.","authors":"Margherita Zipponi, Luciana Cacciottola, Alessandra Camboni, Christina Anna Stratopoulou, Hugh S Taylor, Marie-Madeleine Dolmans","doi":"10.1093/molehr/gaae044","DOIUrl":"10.1093/molehr/gaae044","url":null,"abstract":"<p><p>Adenomyosis is a chronic, estrogen-driven disorder characterized by the presence of endometrial glands and stroma within the myometrium. Despite its significant impact on reproductive health and quality of life, the pathogenesis of the disease remains unclear. Both the glandular and stromal compartments of eutopic endometrium from women with adenomyosis show alterations compared to healthy subjects. However, the molecular mechanisms driving crosstalk between stromal cells and epithelial glands, along with paracrine signaling underlying lesion development and progression, are still poorly understood. Exosomes, small cell-derived carriers and microRNAs, namely non-coding RNA molecules, are crucial to intercellular communication within the endometrium and may elucidate interactions between the two compartments that contribute to adenomyotic lesion formation. To our knowledge, this is the first foundational study to comprehensively isolate and characterize stroma-derived exosomes from women with adenomyosis. Exosome isolation by means of differential ultracentrifugation was validated in 22 samples, including 11 healthy subjects and 11 women with adenomyosis, using nanoparticle tracking analysis, transmission electron microscopy, and flow cytometry. Profiling of microRNA in secreted exosomes revealed 10 microRNAs with significantly altered expression in adenomyosis subjects during the menstrual phase compared to controls. Thorough investigations into menstruation-specific molecular mechanisms, as well as predicted target genes and enriched pathways of exosomal microRNAs, offer promising insights into the pathogenesis of adenomyosis, shedding light on the potential mechanisms underlying stromal cell signaling and adenomyotic lesion establishment. This work does, however, have certain drawbacks, including modest sample size and limited representation due to a lack of readily available endometrial biopsies in the menstrual phase. Having done the groundwork in this study, future research should seek to validate these findings in larger cohorts and apply functional assays. Indeed, our findings can serve as a resource to elucidate the role of menstruation-specific stroma-derived microRNA-mediated signaling and its potential impact on adenomyosis development.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pro-cumulin addition in a biphasic in vitro oocyte maturation system modulates human oocyte and cumulus cell transcriptomes.","authors":"Berta Cava-Cami, Antonio Galvao, Heidi Van Ranst, William A Stocker, Craig A Harrison, Johan Smitz, Michel De Vos, Gavin Kelsey, Ellen Anckaert","doi":"10.1093/molehr/gaaf001","DOIUrl":"10.1093/molehr/gaaf001","url":null,"abstract":"<p><p>Biphasic IVM can be offered as a patient-friendly alternative to conventional ovarian stimulation in IVF patients predicted to be hyper-responsive to ovarian stimulation. However, cumulative live birth rates after IVM per cycle are lower than after conventional ovarian stimulation for IVF. In different animal species, supplementation of IVM media with oocyte-secreted factors (OSFs) improves oocyte developmental competence through the expression of pro-ovulatory genes in cumulus cells. Whether the addition of OSFs in human biphasic IVM culture impacts the transcriptome of oocytes and cumulus cells retrieved from small antral follicles in minimally stimulated non-hCG-triggered IVM cycles remains to be elucidated. To answer this, human cumulus-oocyte complexes (COCs) that were fully surrounded by cumulus cells or partially denuded at the time of retrieval were cultured in a biphasic IVM system either without or with the addition of pro-cumulin, a GDF9:BMP15 heterodimer. Oocytes and their accompanying cumulus cells were collected separately, and single-cell RNA-seq libraries were generated. The transcriptomic profile of cumulus cells revealed that pro-cumulin upregulated the expression of genes involved in cumulus cell expansion and proliferation while downregulating steroidogenesis, luteinization, and apoptosis pathways. Moreover, pro-cumulin modulated the immature oocyte transcriptome during the pre-maturation step, including regulating translation, apoptosis, and mitochondria remodeling pathways in the growing germinal vesicle oocytes. The addition of pro-cumulin also restored the transcriptomic profile of matured metaphase II oocytes that were partially denuded at collection. These results suggest that cumulus cell and oocyte transcriptome regulation by pro-cumulin may increase the number of developmentally competent oocytes after biphasic IVM treatment. Future studies should assess the effects of pro-cumulin addition in human biphasic IVM at the proteomic level and the embryological outcomes, particularly its potential to enhance outcomes of oocytes that are partially denuded at COC collection.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11842067/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A comprehensive study of the sperm head defects in MMAF condition and their impact on embryo development in mice.","authors":"Jana Muroňová, Emeline Lambert, Chanyuth Thamwan, Zeina Wehbe, Magali Court, Geneviève Chevalier, Jessica Escoffier, Zine-Eddine Kherraf, Charles Coutton, Serge Nef, Pierre F Ray, Corinne Loeuillet, Guillaume Martinez, Christophe Arnoult","doi":"10.1093/molehr/gaaf006","DOIUrl":"10.1093/molehr/gaaf006","url":null,"abstract":"<p><p>Among rare cases of teratozoospermia, MMAF (multiple morphological abnormalities of the flagellum) syndrome is a complex genetic disorder involving at least 70 different genes. As the name suggests, patients with MMAF syndrome produce spermatozoa with multiple flagellar defects, rendering them immobile and non-fertilizing, leading to complete infertility in affected men. The only viable treatment option is ICSI. What is less understood is the presence of the various types of head defects in the spermatozoa, which are consistently present. Due to the involvement of numerous genes and the limited number of patients with MMAF syndrome, research on head defects and their impact on embryonic development remains insufficiently explored. To address these questions, a comparative study was conducted under controlled experimental conditions using four knockout (KO) mouse lines targeting Cfap43, Cfap44, Armc2, and Ccdc146 genes, all associated with MMAF syndrome in humans and mice. Each KO line underwent a detailed examination of nuclear defects, including morphology, DNA compaction, chromosomal architecture, and ploidy. The study revealed significant heterogeneity among the four lineages, with the extent of defects varying depending on the lineage, ranked as Ccdc146-/- > Cfap43-/- > Armc2-/- ≈ Cfap44-/-. The developmental potential of sperm from males in each lineage was assessed by injecting them into wild-type oocytes, and embryo development was monitored up to the blastocyst stage. Sperm from all KO lines exhibited a marked decrease in supporting embryo development compared to the wild-type, with developmental failure rates ranked as follows: Ccdc146 > Cfap43 > Armc2 > Cfap44-deficient sperm. The degree of developmental failure thus correlated with the severity of nuclear defects, and zygotes produced with sperm from Ccdc146-/- and Cfap43-/- mice showed the highest rates of developmental impairment. These findings from preclinical models highlight the heterogeneous nature of MMAF syndrome, both in terms of sperm nuclear defects and developmental potentials. Genetic characterization in humans is therefore crucial for improving therapeutic counselling in affected individuals.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143605306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}