Tcte1 knockout influence on energy chain transportation, apoptosis and spermatogenesis – implications for male infertility
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ABSTRACT:
PROVIDER: PRJNA857093 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR20066533_1.fastq.gz | Fastqsanger.gz | |||
| SRR20066533_2.fastq.gz | Fastqsanger.gz | |||
| SRR20066534_1.fastq.gz | Fastqsanger.gz | |||
| SRR20066534_2.fastq.gz | Fastqsanger.gz | |||
| SRR20066535_1.fastq.gz | Fastqsanger.gz |
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Project description:RNA sequencing (RNAseq) in testis tissue has been done to obtain an answer about the influence of Tcte1 null mutation in knockout mice on the expression pattern of other gonadal genes in male animals that may be influential for male fertility status. Homozygous males (infertile) revealed oligoasthenoteratozoospermia (incl. circular pathway of sperm motility), while heterozygous animals (fertile) manifested oligozoospermia, suggesting haploinsufficiency. RNA-sequencing of the mutant testicular tissue showed the influence of Tcte1 mutations on the expression pattern of genes responsible for mitochondrial ATP processing, linked with apoptosis, or spermatogenesis.
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Project description:Spermatogenesis, a fundamental process in male reproduction, is driven by an ordered series of events, which rely on the trafficking of specific proteins between nucleus and cytoplasm. The importin α family of proteins mediates movement of specific cargo proteins when bound to importin β. Importin α genes have distinct expression patterns in mouse testis, implying they may have unique roles during mammalian spermatogenesis. Here we use a loss-of-function approach to specifically determine the role of importin α7 (Kpna6) in spermatogenesis and male fertility. We show that ablation of importin α7 in male mice leads to infertility and has multiple cumulative effects on both germ cells and Sertoli cells culminating in oligozoospermia. Importin α7-deficient mice exhibit an impaired Sertoli cell function, including loss of Sertoli cells from the seminiferous epithelium and a compromised nuclear transport of the androgen receptor. Furthermore, our data demonstrate devastating defects in spermiogenesis that are accompanied by a disturbed histone-protamine-exchange in elongating spermatids, resulting in incomplete sperm maturation and a massive loss of sperms. Our work uncovers the essential role of importin α7 in spermatogenesis and hence in male fertility.
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Project description:Autophagy has been implicated to be involved in spermatogenesis and dysfunction of autophagy can lead to male infertility. However, sophisticated transcriptional signatures of autophagic genes in spermatogenesis and its significance remain uncharacterized. Here, we explore the transcriptional profiling of autophagy-related genes across human spermatogenesis in donors with normal fertility and nonobstructive azoospermia (NOA) patient using single-cell RNA sequencing (scRNA-seq) analysis. Core component gene sets in each step of autophagy exhibit stage-specific expression pattern in human spermatogenesis, which is further confirmed by immunostaining; in this context, we further uncover a unique stage-specific enrichment of a cohort autophagy-related genes. Human-to-mouse comparison analysis reveals that this stage-specific expression pattern of autophagy-related genes is highly conserved in mammals and dysregulation of this pattern is associated with human male infertility. Moreover, we discover several stage-specific autophagic genes, which have not been identified to regulate spermatogenesis before. Among these candidate genes, Cst3, an actively expressed autophagic gene in spermatogonia and early spermatocytes, is involved in the regulation of SSC maintenance and subsequent male germ cell development. Downregulation of Cst3 increases the autophagy activity in mouse SSCs, which exerts its roles by regulating the expression of SSC core factors such as Oct4, Id1 and Nanos3. Collectively, our study provides novel insights into the global transcriptional signatures of autophagy-related genes and confirms the role of proper autophagy activity in SSC maintenance and normal spermatogenesis, opening new avenues for further investigation of the correlation between autophagy and spermatogenesis as well as male infertility.
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Project description:Expression profiling of mouse ing2 -/- testis vs WT reveals gene expression differences consistent with spermatogenic arrest and infertility. Ing2 is indispensable for male germ cell development in mice. While mice deficient for Ing2 were born and grew without apparent abnormalities, male, but not female, were infertile, consistent with the highest expression of Ing2 in testes in wild-type mice and in humans. Histological and DNA content analyses in Ing2-/- testes revealed a spermatogenesis arrest at meiotic phase and enhanced apoptosis associated with increased p53, resulting in a decline in mature spermatozoa, which became more severe in older age. HDAC1 accumulation and core histone deacetylation at pachytene stage were impaired in Ing2-/- testes, suggesting that the recruitment of HDAC1 by Ing2 plays a critical role in spermatogenesis. This study establishes Ing2 as a novel mammalian regulator of spermatocyte differentiation, which coordinates spermatogenesis stage-specific histone modifications. This study has implications in understanding human male infertility.
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