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DIS3 mediated RNA decay is required for maintenance of spermatogenic lineage in mice

ABSTRACT: Spermatogonial stem cells (SSCs) self-renewal and differentiation are the foundation for continious spermatognenesis in mice. Here, we investigate the essential role of DIS3 in maintaining SSC homeostasis and facilitating germ cell differentiation to ensure male fertility. Conditional inactivation of DIS3 in male germ cells have severely impaired SSC self-renewal and differentiation, which results in the failure of spermatogenesis associated with a Sertoli cell-only syndrome and adult sterility. RNA-seq analysis reveals that Dis3 deficiency abolishes its nucleolytic activity and causes significant dysregulation of the expression of transcripts in Dis3 mutant testes. We have also found that the pervasive transcription products described previously, such as Promoter Upstream Transcripts (PROMPTs), accumulate robustly upon DIS3 dysfunction in Dis3 cKO testes. In addition, scRNA-seq analysis indicates that DIS3 mutation significantly impairs germline stem cell development that blocks stem cell proliferation and differentiation. Overall, we show that DIS3 ribonuclease plays a critical role in the maintenance of spermatogenic lineage during spermatogenesis in mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE158190 | GEO | 2021/07/15

REPOSITORIES: GEO

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DIS3 ribonuclease is required for the maintenance of spermatogenic lineage in mice

Project description:Spermatogonial stem cells (SSCs) self-renewal and differentiation are the foundation for continious spermatognenesis in mice. Here, we investigate the essential role of DIS3 in maintaining SSC homeostasis and facilitating germ cell differentiation to ensure male fertility. Conditional inactivation of DIS3 in male germ cells have severely impaired SSC self-renewal and differentiation, which results in the failure of spermatogenesis associated with a Sertoli cell-only syndrome and adult sterility. RNA-seq analysis reveales that Dis3 deficiency abolishes its nucleolytic activity and causes significant dysregulation of the expression of transcripts in Dis3 mutant testes. We have also found that the pervasive transcription products described previously, such as Promoter Upstream Transcripts (PROMPTs), accumulate robustly upon DIS3 dysfunction in Dis3 cKO testes. In addition, scRNA-seq analysis indicates that DIS3 mutation significantly impairs germline stem cell development that blocks stem cell proliferation and differentiation. Overall, we show that DIS3 ribonuclease plays a critical role in the maintenance of spermatogenic lineage during spermatogenesis in mice.

2020-08-20 | GSE156505 | GEO

DIS3 is essential for male germ cell meiosis and spermatogenesis in mice

Project description:Male germ cell meiosis is essential for generating haploid spermatozoa in mice. Here, we investigate the essential role of DIS3 in male germ cell meiosis in mice. Conditional inactivation of DIS3 in spermatocytes with Stra8-cre transgenic mice have severely impaired meiotic progression, which results in defective meiosis and spermatogenesis. RNA-seq analysis reveals that Dis3 deficiency causes significant dysregulation of the expression of transcripts in mutant testes. Meiosis-associated genes are significantly decreased in the absence of DIS3. Therefore, we show that DIS3 ribonuclease plays a critical role in germ cell meiosis during spermatogenesis in mice.

2021-07-16 | GSE180197 | GEO

Gene expression profiles of Lhcgr-deficient testes

Project description:Spermatogonial stem cells (SSCs) provide foundation for spermatogenesis by undergoing continuous self-renewal division. Previous studies have reported conflicting results on the role of the pituitary gland activity in SSC self-renewal. In this study, we analyzed the role of hormonal regulation of SSCs using Lhcgr (luteinizing hormone/choriogonadotropin receptor) knockout mice. Analysis of gene expression profiles showed that testes of Lhcgr-deficient mice exhibit significantly enhanced Wnt5a expression in Sertoli cells. Lhcgr KO and control WT mice were treated with busulfan in order to eliminate germ cells. The total RNA samples from their testes were subjected to microarray analysis to compare their gene expression profiles.

2016-07-15 | E-GEOD-77500 | biostudies-arrayexpress

Splicing factor SRSF1 is essential for homing of precursor spermatogonial stem cells in mice

Project description:Spermatogonial stem cells (SSCs) provide a continuous spermatogenesis and male fertility. However, the underlying mechanisms of alternative splicing (AS) in mouse SSCs are still largely unclear. We demonstrated that SRSF1 is essential for gene expression and splicing in mouse SSCs. Specific deletion of Srsf1 in mouse germ cells impairs self-renewal and homing of SSCs leading to male infertility. Whole-mount staining data showed the absence of germ cells in the testes of adult cKO mice, which indicates severe non-obstructive azoospermia (NOA) in cKO mice. Expression of SSC-related genes (Gfra1, Pou5f1, Plzf, Dnd1, Stra8, and Taf4b) was significantly reduced in the testes of conditional knockout (cKO) mice. CLIP-seq data found that SSC-related genes (Plzf, Id4, Setdb1, Stra8, Tial1, Bcas2, Ddx5, Srsf10, Uhrf1, and Bud31) were bound by SRSF1 in the mouse testes. Moreover, multi-omics analysis suggests that SRSF1 directly binds and regulates the expression of Tial1 via AS to implement SSCs self-renewal and differentiation. Collectively, our data reveal the critical role of an SRSF1-mediated AS in SSCs self-renewal and differentiation, which may provide a framework to elucidate the molecular mechanisms of the post-transcriptional network underlying SSCs.

2024-01-08 | GSE227575 | GEO

Gene expression profiles of Lhcgr-deficient testes

2016-07-15 | GSE77500 | GEO

Transcriptomic profiling of young and aged spermatogonial stem cells (RNA-Seq)

Project description:Spermatogonial stem cells (SSC), the foundation of spermatogenesis and male fertility, possess lifelong self-renewal activity. Aging leads to the decline in stem cell function and increased risk of paternal age-related genetic diseases. In the present study, we performed a comparative genomic analysis of mouse SSC (Oct4-GFP+/KIT-) and differentiating progenitors (Oct4-GFP+/KIT+) isolated from young and aged testes. Our transcriptome data revealed enormous complexity of expressed coding and non-coding RNAs and alternative splicing regulation during SSC differentiation. Further comparison between young and aged SSCs suggested these differentiation programs were affected by aging. We identified aberrant expression of genes associated with meiosis and TGF-β signaling , alteration in alternative splicing regulation and differential expression of specific lncRNAs such as Fendrr.

2021-06-14 | GSE164604 | GEO

Lovastatin Promotes the Self-renewal of Murine and Primate Spermatogonial Stem Cells

Project description:The spermatogonial stem cells (SSCs) niche is critical for SSC maintenance and the subsequent spermatogenesis. Numerous reproductive hazards impair the SSC niche, thereby result in aberrant SSC self-renewal and male infertility. However, promising agents targeting the impaired SSC niche to promote SSC self-renewal are still limited. Here, we screen out and assess the effects of Lovastatin on the self-renewal of mouse spermatogonial stem cells (mSSCs). Mechanistically, Lovastatin promotes the self-renewal of mSSCs and inhibits its inflammation and apoptosis through the regulation of isoprenoid intermediates. Likewise, other statins exhibit similar effects on SSC self-renewal. Remarkably, the treatment by Lovastatin could promote the self-renewal of mSSCs in the male gonadotoxicity model generated by busulfan injection. Noteworthy, we demonstrate that Lovastatin could significantly enhance the self-renewal of in vitro cultured primate SSCs. Collectively, our findings uncover that lovastatin could promote the self-renewal of both murine and primate SSCs and have implications for the treatment of certain male infertility using small compounds.

2022-06-10 | GSE182897 | GEO

Epigenetic profiling of young and aged spermatogonial stem cells (ChIP-Seq)

2021-06-14 | GSE164603 | GEO

UXT is required for spermatogenesis in mice

Project description:Male mammals must simultaneously produce prodigious numbers of sperm and maintain an adequate reserve of stem cells to ensure continuous production of gametes throughout life. Failures in the mechanisms responsible for balancing germ cell differentiation and spermatogonial stem cell (SSC) self-renewal can result in infertility. We discovered a novel requirement for Ubiquitous Expressed Transcript (UXT) in spermatogenesis by developing the first knockout mouse model for this gene. Constitutive deletion of Uxt is embryonic lethal, while conditional knockout in the male germline results in a Sertoli cell-only phenotype during the first wave of spermatogenesis that does not recover in the adult. This phenotype begins to manifest between 6 and 7 days post-partum, just before meiotic entry. Gene expression analysis revealed that Uxt deletion downregulates the transcription of genes governing SSC self-renewal, differentiation, and meiosis, consistent with its previously defined role as a transcriptional co-factor. Our study has revealed the first in vivo function for UXT in the mammalian germline as a regulator of distinct transcriptional programs in SSCs and differentiating spermatogonia.

2018-04-18 | GSE111740 | GEO

Retinoic acid-induced differentiation of porcine spermatogonia in vitro

Project description:Spermatogenesis is an intricate developmental process occurring in testes by which spermatogonial stem cells (SSCs) self-renew and differentiate into mature sperm. The molecular mechanisms for SSC self-renewal and differentiation, while have been well studied in mice, may differ between mice and domestic animals including pigs. To gain knowledge about the molecular mechanisms for porcine SSC self-renewal and differentiation that have to date been poorly understood, here we isolated and enriched primitive spermatogonia from neonatal porcine testes, and exposed the cells to retinoic acid, a direct inducer for spermatogonial differentiation. We then identified that retinoic acid could induce porcine primitive spermatogonial differentiation into leptotene spermatocyte-like cells, which was accompanied by a clear transcriptomic alteration, as revealed by the RNA-sequencing analysis. We also compared retinoic acid-induced in vitro porcine spermatogonial differentiation with the in vivo process, and compared retinoic acid-induced in vitro spermatogonial differentiation between pigs and mice. Furthermore, we analyzed retinoic acid-induced differentially expressed long non-coding RNAs (lncRNAs), and demonstrated that a pig-specific lncRNA, lncRNA-106504875, positively regulated porcine spermatogonial proliferation by targeting the core transcription factor ZBTB16. Taken together, these results would help to elucidate the roles of retinoic acid in porcine spermatogonial differentiation, thereby contributing to further knowledge about the molecular mechanisms underlying porcine SSC development and, in the long run, to optimization of both long-term culture and induced differentiation systems for porcine SSCs.

2023-01-09 | GSE219031 | GEO

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