Similar Datasets
Project description:Alternative splicing-induced inclusion of poison exons containing in-frame stop codons is a mechanism that can be used to attenuate gene expression. Poison exon have been implicated in cancer, but how they operate within the context of normal development and physiology is poorly understood. Several splicing regulator genes, including Tra2b, contain ultra-conserved poison exons that function within regulatory loops to fine-tune their activity. To investigate the physiological role of poison exons in vivo, we created mice lacking either Tra2b or its poison exon, specifically during spermatogenesis to reveal both are essential for male fertility. The mouse Tra2b gene is essential for mitotic proliferation of germ cells, whereas, in contrast, the Tra2b poison exon is critically required during meiosis and not needed by mitotically proliferating cell populations within the germline. Poison exon deletion causes infertility, with a block in male meiotic prophase where Tra2β protein expression levels normally increase. Deletion of the Tra2b poison exon changes expression patterns of genes important for meiosis and splicing patterns of Tra2β target exons, suggesting Tra2b poison exon splicing prevents meiotic cells accumulating toxic levels of Tra2b expression. Our data provide a new physiological explanation for Tra2b poison exon ultra-conservation and indicate the importance of evaluating poison exon function within a physiological context.
2024-12-19 | GSE235084 | GEO
Project description:Alternative splicing-induced inclusion of poison exons containing in-frame stop codons is a mechanism that can be used to attenuate gene expression. Poison exon have been implicated in cancer, but how they operate within the context of normal development and physiology is poorly understood. Several splicing regulator genes, including Tra2b, contain ultra-conserved poison exons that function within regulatory loops to fine-tune their activity. To investigate the physiological role of poison exons in vivo, we created mice lacking either Tra2b or its poison exon, specifically during spermatogenesis to reveal both are essential for male fertility. The mouse Tra2b gene is essential for mitotic proliferation of germ cells, whereas, in contrast, the Tra2b poison exon is critically required during meiosis and not needed by mitotically proliferating cell populations within the germline. Poison exon deletion causes infertility, with a block in male meiotic prophase where Tra2β protein expression levels normally increase. Deletion of the Tra2b poison exon changes expression patterns of genes important for meiosis and splicing patterns of Tra2β target exons, suggesting Tra2b poison exon splicing prevents meiotic cells accumulating toxic levels of Tra2b expression. Our data provide a new physiological explanation for Tra2b poison exon ultra-conservation and indicate the importance of evaluating poison exon function within a physiological context.
2024-12-19 | GSE235083 | GEO
Project description:The cellular concentrations of splicing factors (SFs) are critical for controlling alternative splicing. Most serine and arginine-enriched (SR) protein SFs regulate their own concentration via a homeostatic feedback mechanism that involves regulation of inclusion of non-coding 'poison exons' (PEs) that target transcripts for nonsense-mediated decay. The importance of SR protein PE splicing during animal development is largely unknown despite PE ultra-conservation across animal genomes. To address this, we used mouse genetics to disrupt an ultra-conserved PE in the Tra2b gene encoding the SR protein Tra2β. Focussing on germ cell development, we found that Tra2b PE deletion causes azoospermia due to catastrophic cell death during meiotic prophase. Failure to proceed through meiosis was associated with increased Tra2b expression sufficient to drive aberrant Tra2β protein hyper-responsive splice patterns. Although critical for meiotic prophase, Tra2b PE deletion spared earlier mitotically active germ cells, even though these still required Tra2b gene function. Our data indicate that PE splicing control prevents the accumulation of toxic levels of Tra2β protein that are incompatible with meiotic prophase. This unexpected connection with male fertility helps explain Tra2b protein PE ultra-conservation and indicates the importance of evaluating PE function in animal models.
| S-SCDT-10_1038-S44318-024-00344-6 | biostudies-other
Project description:An essential role for the ultra-conserved poison exon of Tra2b in fertility in mice
| PRJNA984307 | ENA
Project description:An essential role for the ultra-conserved poison exon of Tra2b in fertility in mice (RNA-seq)
| PRJNA984310 | ENA
Project description:An essential role for the ultra-conserved poison exon of Tra2b in fertility in mice (iCLIP-seq)
| PRJNA984309 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-06-01 | GSE267609 | GEO
Project description:Sphingolipids and the derived gangliosides have critical functions in spermatogenesis, thus mutations in genes involved in sphingolipid biogenesis are often associated with male infertility. We have generated a transgenic mouse line carrying an insertion in the sphingomyelin synthase gene Sms1, the enzyme which generates sphingomyelin species in the Golgi apparatus. We describe the spermatogenesis defect of Sms1-/- mice, which is characterized by sloughing of spermatocytes and spermatids, causing progressive infertility of male homozygotes. Lipid profiling revealed a reduction in several long chain unsaturated phosphatidylcholins, lysophosphatidylcholins and sphingolipids in the testes of mutants. Multi-Spectral Optoacoustic Tomography indicated blood-testis barrier dysfunction. A supplementary diet of the essential omega-3 docosahexaenoic acid and eicosapentaenoic acid diminished germ cell sloughing from the seminiferous epithelium and restored spermatogenesis and fertility in 50% of previously infertile mutants. Our findings indicate that SMS1 has a wider than anticipated role in testis polyunsaturated fatty acid homeostasis and for male fertility.
| S-EPMC5082796 | biostudies-literature
Project description:The recombinase RAD51 catalyzes the DNA strand exchange reaction in homologous recombination (HR) during both mitosis and meiosis. However, the physiological role of RAD51 during spermatogenesis remains unclear since RAD51 null mutation is embryonic lethal in mice. In this study, we generated a conditional knockout mouse model to study the role of RAD51 in spermatogenesis. Conditional disruption of RAD51 in germ cells by Vasa-Cre led to spermatogonial loss and Sertoli cell-only syndrome. Furthermore, tamoxifen-inducible RAD51 knockout by UBC-CreERT2 confirmed that RAD51 deletion led to early spermatogenic cells loss and apoptosis. Notably, inducible knockout of RAD51 in adult mice caused defects in meiosis, with accumulated meiotic double-strand breaks (DSBs), reduced numbers of pachytene spermatocytes and less crossover formation. Our study revealed an essential role for Rad51 in the maintenance of spermatogonia as well as meiotic progression in mice.
| S-EPMC8924220 | biostudies-literature
Project description:Patients with teratozoospermia exhibit low phosducin-like protein (Pdcl2) expression. As a member of the phosducin family, chaperonin-related Pdcl2, a germline-specific gene, may be involved in germ cell protein folding. Given that PDCL2 is highly conserved in evolution, it may be indispensable for mammalian spermiogenesis; however, the function of PDCL2 in higher mammalian species remains unknown. To determine the role of PDCL2 in male fertility, we generated Pdcl2 knockout mice using CRISPR/Cas9. Our results revealed that Pdcl2 heterozygous (Pdcl2+/-) male mice were normal, but male Pdcl2-null (Pdcl2-/-) mice were infertile. Accordingly, Pdcl2-/- male mice exhibited lower testis weight, epididymis weight, and sperm number than Pdcl2+/+ mice. Moreover, Pdcl2-/- mice displayed malformed and immotile sperm. Apoptotic cells were significantly enhanced in Pdcl2-/- testes and epididymis when compared with those in wild-type mice. Mechanistically, PDCL2 can interact with the CCT complex, and dysfunction in this complex might lead to infertility in Pdcl2-/- male mice. Collectively, these findings confirm that Pdcl2 knockout leads to male infertility in mice and that PDCL2 may function as a chaperone to promote protein folding during spermiogenesis.
| S-EPMC9576706 | biostudies-literature