Mouse Testis IP-MS Analysis of TEX44 Interacting Proteins
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus Musculus
SUBMITTER: 
Mingxi Liu
PROVIDER: PXD060989 | iProX | Thu Feb 20 00:00:00 GMT 2025
REPOSITORIES: iProX
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Project description:Investigation of a new RNA-modification-based mechanism in mammalian spermatogenesis. We created a mice line devoid of testis-specific m5C RNA methyltransferase Nsun7. These mice demonstrated male infertility due to a peculiar defect in sperm tail assembly – mispositioning of the longitudinal columns of the fibrous sheath. The whole testis proteomes of wild type and Nsun7 knockout mice were obtained to study the molecular pathways affected by NSUN7.
2025-03-07 | PXD057007 | Pride
Project description:STUDY QUESTION: What are the causative genetic variants in patients with male infertility due to severe sperm motility disorders?
SUMMARY ANSWER: We identified high confidence disease-causing variants in multiple genes previously associated with severe sperm motility disorders in 9 out of 21 patients (43%). We also identified variants in novel candidate genes in 8 additional patients (38%).
WHAT IS KNOWN ALREADY: Severe sperm motility disorders are a form of male infertility characterised by vital, but immotile sperm often in combination with a spectrum of structural abnormalities of the sperm flagellum. Examples of this spectrum of disorders include dysplasia of the fibrous sheath / multiple morphological abnormalities of the sperm flagella (DFS-MMAF) and severe forms of asthenozoospermia associated to non-specific structural defects. These disorders frequently recur in families and may include chronic respiratory disease. As such, genetic causes are suspected and many genes have recently been reported. Currently, depending on the clinical sub-categorisation, up to 50% of causality in patients with severe sperm motility disorders can be explained by pathogenic variants in at least 21 known genes.
STUDY DESIGN, SIZE, DURATION: We performed exome sequencing in patients with severe sperm motility disorders from two different clinics, aiming to identify the underlying genetic defects and establishing a diagnostic yield in both.
PARTICIPANTS/MATERIALS, SETTING, METHOD: Two groups of infertile men, one from Argentina (n= 9) and one from Australia (n=12), with clinically defined sperm motility disorders were included. All patients in the Argentine cohort were diagnosed with DFS-MMAF, based on transmission electron microscopy. Exome sequencing was performed in all 21 patients and variants with an allele frequency of <1% in the gnomAD population were prioritised and interpreted.
MAIN RESULTS AND ROLE OF CHANCE: In 9/21 patients (43%), we identified pathogenic variants in known sperm motility disorder genes: CFAP43 (3 patients); CFAP44 (2 patients), QRICH2 (2 patients), DNAH1 (1 patient) and DNAH6 (1 patient). The diagnostic rate did not differ markedly between the Argentinian and the Australian cohort (44% and 42%, respectively). Furthermore, we identified patients with variants in the novel candidate sperm motility genes CFAP58, DNAH12, DRC1, MDC1, PACRG, SSPL2C and TPTE2. One patient presented with two possibly damaging variants in four candidate genes and it remains unclear which variants were responsible for the severe sperm motility defect in this patient.
LIMITATIONS, REASONS FOR CAUTION: In this study, we described patients with potential bi-allelic variants in known and novel candidate genes for severe sperm motility disorders. Due to unavailability of parental DNA, we have not assessed de novo or maternally inherited dominant variants and could not phase the mutations to establish in all cases that the mutations occur on both alleles.
WIDER IMPLICATIONS OF THE FINDINGS: Our results confirm an important role for five known genes for sperm motility and we demonstrate that exome sequencing is an effective method to diagnose patients with severe sperm motility defects (9/21 diagnosed; 43%). Furthermore, our analysis revealed seven novel candidate genes for severe sperm motility disorders. Genome-wide sequencing of additional patient cohorts and re-analysis of exome data of currently unsolved cases may reveal additional variants in these novel candidate genes.
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Project description:JQ1 is a small-molecule (BET family) bromodomain inhibitor that causes a contraceptive effect in mice by blocking spermatogenesis and reducing sperm motility.
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Project description:Sperm motility is one of the most important indicator for evaluating roosters’ fecundity. However, the molecular regulation underlying chicken sperm motility is not yet clear. MicroRNA (miRNA) plays epigenetic roles in reproduction. In this study, we compared the testicular miRNAs of Beijing-you roosters with high (HS) and low (LS) sperm motility using Solexa sequencing. Length distribution analysis showed that the dominant size of the small RNAs detected in the testis was 24~28 nt. In total, 518 known and 106 novel miRNAs were identified. A number of 23 miRNAs were found differentially expressed (P < 0.05, |log2fold change| ≥ 1) between the HS and LS, including 18 known and five novel miRNAs. Function enrichment of predicted target genes of the differential miRNAs indicated that the differentially expressed miRNAs were involved in the pathways of GnRH signaling, MAPK signaling, and Wnt signaling. The miRNA-gene interaction network revealed two key candidate miRNA-gene pairs that may affect chicken sperm motility viz gga-miR-155/KCNA1 and gga-miR-7480-5p/AHI1. qRCR was also used to further validate their expression. The results here provide deep insight into the expression of miRNA in the testis of chicken and suggest their roles in sperm motility regulation.
2018-01-13 | GSE109141 | GEO
Project description:Asthenoteratozoospermia is a major cause of male infertility. Thus far, the identified related genes can explain only a small share of asthenoteratozoospermia cases, suggesting the involvement of other genes. The transmembrane protein TMEM232 is highly expressed in mouse testes. In the present study, to determine its function of TMEM232 in testes, we constructed a Tmem232-null mouse model using CRISPR–Cas9 technology. Tmem232 knockout (KO) male mice was completely infertile, and their sperm were immotile, with morphological defects of the flagellum. Electron microscopy revealed an aberrant midpiece-principal junction and the loss of the fourth of nine doublet microtubules in the sperm of Tmem232-/-mice. Sperm cells presented an 8+2 conformation and an irregular arrangement of the mitochondrial sheath. Proteomic analysis indicated a downregulation in the expression of proteins associated with flagellar motility, sperm capacitation, and the integrity and stability of sperm structure, as well as an upregulation in the expression of multiple ribosome components in TMEM232-deficient spermatids. Additionally, TMEM232 was observed to be involved in ribophagy by interacting with autophagy-related proteins, such as ATG14 and ARMC3, to regulate ribosome homeostasis during spermiogenesis. These results suggest that TMEM232 is essential for normal sperm flagellum formation and plays an important role in the autophagic elimination of cytosolic ribosomes to provide energy for flagellar motility.
2024-06-06 | GSE268908 | GEO
Project description:In this study, chromatin immunoprecipitated sequencing was done for testis specific histone variants of H2B and H2A, TH2B and TH2A to understand the epigenomics of these retained histones, using murine caudal sperm.Our in silico analysis has attributed a myriad of novel functions to sperm retained TH2B with respect to embryo development and spermatogenesis.Also, based on genomic regions, TH2B was observed to be associated with spindle assembly and various meiosis-specific genes, which is an important finding as TH2A/TH2B DKO mice have been reported to have defective cohesin release.We also observed a degree of evolutionary conservation between the TH2B-DNA linkage across human and mouse.This overlap included genes important for embryogenesis. Most importantly, heterogeneity in the epigenetic landscape of TH2A and TH2B was seen which is intriguing as TH2B and TH2A are well reported to be present in the same nucleosomes to promote open chromatin. Additionally, unlike TH2B, TH2A was enriched on the mitochondrial chromosome. We presume that TH2A is associated with mitochondrial DNA inserted in the nuclear DNA and this observation needs further validation.. A comprehensive analysis of these observations indicates novel functions for the sperm retained TH2B and TH2A.
2021-12-06 | GSE181921 | GEO
Project description:PKA signaling plays important functions during mouse spermatogenesis and for the regulation of sperm motility. The efficiency of PKA signaling is regulated partly by its binding protein A-kinase anchoring protein (AKAP) family. Mature mouse sperm contain several AKAPs, of which AKAP3 and AKAP4 are localized in the principal piece of sperm tail and they are sperm-specific. Using gene knock-out mouse models, it was found that both AKAP3 and AKAP4 are essential for the formation of a complete fibrous sheath, the electron-dense sub-cellular structure within sperm flagellum that is important for the motility of sperm and male fertility. Lack of AKAP3 or AKAP4 caused aberrant sperm morphology and inmotility, leading to eventual male sterility. In the present study, we investigated the changes of cellular proteome in the absence of AKAP3 or AKAP4 in mature sperm, using quantitative mass spectrometry. It was found that global changes of sperm proteome occur in the absence of AKAP3 or AKAP4. In Akap3 null sperm, proteins related to flagella structure, PKA signaling and motility regulations are down-regulated, whereas proteins involved in RNA metabolism, protein translation and actin filaments formation are accumulated. Akap4 null sperm also displayed changes of sperm proteome at lesser extends. These results suggest that both AKAP3 and AKAP4 are essential for the formation of sperm sub-cellular structures, proper regulation of PKA activity and motility of sperm, providing new clues to elucidate the molecular pathways that underlie the coordinated synthesis and organization of sperm proteome and sperm morphology
2020-01-14 | PXD016928 | Pride
Project description:Phosphoprotein phosphatase 1 catalytic subunit gamma 2 (PPP1CC2), a PPP1 isoform restricted to testicular germ cells and spermatozoa, is essential for completion of spermatogenesis and highly similar PPP1C isoforms are capable of compensating for the loss of Ppp1cc in every tissue except in testis. In addition, inhibition of the enzymatic activity of PPP1C in spermatozoa stimulates motility. The key to understand the regulation of PPP1CC2 lies in the identification and characterization of its interacting partners. By integrating tissue-specific protein expression and protein-protein interaction data, we identified testis/sperm-enriched/specific PPP1CC complexes and potential key PPP1 interacting proteins (PIPs) for male reproduction. We constructed a testis/sperm-enriched network, analyzed several topological properties and specified the biological/physiological properties of the proteins in the network. Proteins were classified into modules according to their topological features and functional annotations, which clarified the mechanisms underlying testis and sperm function and, more specifically, the role of PPP1CC in spermatogenesis and sperm motility. Previously uncharacterized PIPs, such as AKAP4, were identified based on analyses of the interaction network. The PPP1CC2 interaction with AKAP4 in human sperm was also validated by different methods and the complex was proposed as potential targets for male contraception due to its significance in spermatozoa motility.
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Project description:Long non-coding RNAs are known to play crucial roles in various physiological processes in mammals, yet their functions in spermatogenesis remain largely underexplored. Here, we have identified a distinct category of conserved haploid spermatids-associated long non-coding RNAs (cHS-LncRNAs) characterized by their sequence-based conservation, specific expression in the testis, and elevated expression levels in haploid spermatids. Among these, we found that the testis specific conserved LncRNA 1 (Tscl1) exhibits the highest expression in round spermatids. Deletion of Tscl1 in mice exhibits reduced sperm motility, disordered mitochondrial sheath structure, abnormal fatty acid metabolism, and results in male infertility. Mechanistically, Tscl1 directly interacts with PIWIL1 and HuR via its 5′ end stem-loop structure and multiple AU-rich elements, respectively. This binding pattern promotes the formation of the PIWIL1/eIF3f/HuR/eIF4G3 supercomplex, regulating the translation efficiency of fatty acid metabolism-associated mRNAs within the chromatoid body. Furthermore, the region where TSCL1 interacts with PIWIL1 is significantly enriched with TSCL1 variants identified in patients with non-obstructive azoospermia (NOA) compared to those in the fertile controls (OR=5.992, P=0.020, NCase=1,338, NControl=2,664). Taken together, our findings elucidate the critical role of Tscl1 in regulating the translation efficiency of target mRNAs through its collaboration with PIWIL1 and HuR during spermiogenesis.
2024-12-17 | GSE284143 | GEO
Project description:Long non-coding RNAs are known to play crucial roles in various physiological processes in mammals, yet their functions in spermatogenesis remain largely underexplored. Here, we have identified a distinct category of conserved haploid spermatids-associated long non-coding RNAs (cHS-LncRNAs) characterized by their sequence-based conservation, specific expression in the testis, and elevated expression levels in haploid spermatids. Among these, we found that the testis specific conserved LncRNA 1 (Tscl1) exhibits the highest expression in round spermatids. Deletion of Tscl1 in mice exhibits reduced sperm motility, disordered mitochondrial sheath structure, abnormal fatty acid metabolism, and results in male infertility. Mechanistically, Tscl1 directly interacts with PIWIL1 and HuR via its 5′ end stem-loop structure and multiple AU-rich elements, respectively. This binding pattern promotes the formation of the PIWIL1/eIF3f/HuR/eIF4G3 supercomplex, regulating the translation efficiency of fatty acid metabolism-associated mRNAs within the chromatoid body. Furthermore, the region where TSCL1 interacts with PIWIL1 is significantly enriched with TSCL1 variants identified in patients with non-obstructive azoospermia (NOA) compared to those in the fertile controls (OR=5.992, P=0.020, NCase=1,338, NControl=2,664). Taken together, our findings elucidate the critical role of Tscl1 in regulating the translation efficiency of target mRNAs through its collaboration with PIWIL1 and HuR during spermiogenesis.
2024-12-17 | GSE284142 | GEO