SRSF1 is involved in alternative mRNA splicing in granulosa cell survival
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE228975 | GEO | 2024/01/01
REPOSITORIES: GEO
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Project description:Serine/arginine-rich splicing factor 1 (SRSF1; previously SF2/ASF) is a pivotal posttranscriptional regulator of gene expression in various biological processes. However, the physiological roles and mechanism of SRSF1 in mouse early-stage oocytes remain elusive. Here we show that SRSF1 is essential for primordial follicle formation and number determination during meiotic prophase I. The conditional knockout of Srsf1 in mouse oocytes impairs primordial follicle formation and leads to primary ovarian insufficiency (POI). Oocyte-specific genes (e.g., LHX8, NOBOX, SOHLH1, SOHLH2, FIGLA, KIT, JAGGED1, and RAC1) that regulate primordial follicle formation are suppressed in newborn Stra8-GFPCre Srsf1Fl/Fl (cKO) mouse ovaries. However, meiotic defects are the leading cause of abnormal primordial follicle formation. In cKO mouse ovaries, immunofluorescence results suggest that the failure of synapsis and the inability to undergo recombination result in fewer homologous DNA crossovers (COs). Moreover, SRSF1 directly binds and regulates the expression of the POI-related genes Six6os1 and Msh5 via alternative splicing to implement the meiotic prophase I program. Altogether, our data reveal a critical role of the SRSF1-mediated posttranscriptional regulatory mechanism in the mouse oocyte meiotic prophase I program, which provides a framework to elucidate molecular mechanisms of the posttranscriptional network underlying primordial follicle formation.
2023-02-06 | GSE198205 | GEO
Project description:It has previously been shown that FOXL2 and ESR1 cooperate to repress the testis-determining gene Sox9 in murine granulosa cells, and suggested that FOXL2/ESR1 cooperation may be central to granulosa cell differentiation (Uhlenhaut et al., 2009). However, no study has so far compared the DNA-binding of FOXL2 and ESR1 at the genomic level or analyzed the impact of FOXL2 on ESR1 binding to its regulatory elements. Here, we have analyzed and compared the genomic locations recognized by ESR1 and FOXL2 in E2-treated primary murine granulosa cells. Input DNA, FOXL2 and ESR1 ChIP
2015-07-01 | E-GEOD-62545 | biostudies-arrayexpress
Project description:FOXL2 is a transcription factor essential for female fertility, expressed in somatic cells of the ovary, notably granulosa cells. In the mouse, Foxl2 deletion leads to partial sex reversal postnatally. However, deletion of the gene in 8-week-old females leads to granulosa to Sertoli cell transdifferentiation. We hypothesised that different outcomes of Foxl2 deletion in embryonic versus adult ovary may depend on a different role played across ovarian development. Therefore, we characterised the dynamics of gene expression and chromatin accessibility changes in purified murine granulosa cells across key developmental stages (E14.5, 1 and 8 weeks). We then performed genome-wide identification of FOXL2 target genes and on-chromatin interacting partners by ChIP-SICAP. We found that FOXL2 regulates more genes at postnatal stages, through the interaction with factors regulating primordial follicle activation (PFA), such as NR5A2, and others regulating steroidogenesis including AR and ESR2. As a proof of principle experiment, we chose one FOXL2 interactor, Ubiquitin specific protease 7 (USP7) and showed that deletion of this gene in granulosa cells leads to a blockage of PFA, impaired ovary development and sterility. Our study constitutes a comprehensive resource for exploration of the molecular mechanisms of ovarian development and causes of female infertility.
2024-03-25 | PXD043951 | Pride
Project description:FOXL2 is a transcription factor essential for female fertility, expressed in somatic cells of the ovary, notably granulosa cells. In the mouse, Foxl2 deletion leads to partial sex reversal postnatally, with mutants developing dysgenic ovaries devoid of oocytes. However, deletion of the gene in 8-week-old females leads to granulosa to Sertoli cell transdifferentiation and gonadal sex reversal. We hypothesise that different outcomes of Foxl2 deletion in embryonic versus adult ovary may depend on a different role played by FOXL2 across ovarian development. Therefore, in this study, we take a multi-omics approach to characterise the dynamics of gene expression and chromatin accessibility changes in purified murine granulosa cells across key developmental stages (E14.5, 1 and 8 weeks). We coupled these analyses with genome wide identification of FOXL2 target genes and on-chromatin interacting partners by ChIP-SICAP to reconstruct the gene regulatory networks underpinned by this essential transcription factor and to discover novel players. We found that, in the embryonic ovary, FOXL2 interacts with factors important for early stages of gonadal development, such as GATA4 and WT1, whilst postnatally it interacts with factors regulating primordial follicle activation, such as NR5A2, and with factors regulating steroidogenesis including AR and ESR2. Integration of chromatin landscape dynamics with gene expression changes and FOXL2 binding sites analysis revealed that its critical role in ovarian cell fate maintenance goes beyond repression of the Sertoli-specific gene Sox9. Our chromatome analysis revealed also that FOXL2 interacts with several proteins involved in chromatin remodelling, DNA repair, splicing and gene repression. We identified a FOXL2 interactor with a role in primordial follicle activation, Ubiquitin specific protease 7 (USP7). We showed that conditional deletion of this gene in granulosa cells leads to a blockage of primordial follicle activation, impairs ovary development and leads to complete sterility. In summary, in this study we identified target genes dynamically regulated by FOXL2 across ovarian development including known and newly identified FOXL2 targets with a role in embryonic ovarian development and folliculogenesis, as well as cofactors that point towards additional roles played by FOXL2 besides transcriptional regulation. This work constitutes a comprehensive resource for exploration of the molecular mechanisms of ovarian development and causes of female infertility.
2024-03-24 | GSE236785 | GEO
Project description:FOXL2 is a transcription factor essential for female fertility, expressed in somatic cells of the ovary, notably granulosa cells. In the mouse, Foxl2 deletion leads to partial sex reversal postnatally, with mutants developing dysgenic ovaries devoid of oocytes. However, deletion of the gene in 8-week-old females leads to granulosa to Sertoli cell transdifferentiation and gonadal sex reversal. We hypothesise that different outcomes of Foxl2 deletion in embryonic versus adult ovary may depend on a different role played by FOXL2 across ovarian development. Therefore, in this study, we take a multi-omics approach to characterise the dynamics of gene expression and chromatin accessibility changes in purified murine granulosa cells across key developmental stages (E14.5, 1 and 8 weeks). We coupled these analyses with genome wide identification of FOXL2 target genes and on-chromatin interacting partners by ChIP-SICAP to reconstruct the gene regulatory networks underpinned by this essential transcription factor and to discover novel players. We found that, in the embryonic ovary, FOXL2 interacts with factors important for early stages of gonadal development, such as GATA4 and WT1, whilst postnatally it interacts with factors regulating primordial follicle activation, such as NR5A2, and with factors regulating steroidogenesis including AR and ESR2. Integration of chromatin landscape dynamics with gene expression changes and FOXL2 binding sites analysis revealed that its critical role in ovarian cell fate maintenance goes beyond repression of the Sertoli-specific gene Sox9. Our chromatome analysis revealed also that FOXL2 interacts with several proteins involved in chromatin remodelling, DNA repair, splicing and gene repression. We identified a FOXL2 interactor with a role in primordial follicle activation, Ubiquitin specific protease 7 (USP7). We showed that conditional deletion of this gene in granulosa cells leads to a blockage of primordial follicle activation, impairs ovary development and leads to complete sterility. In summary, in this study we identified target genes dynamically regulated by FOXL2 across ovarian development including known and newly identified FOXL2 targets with a role in embryonic ovarian development and folliculogenesis, as well as cofactors that point towards additional roles played by FOXL2 besides transcriptional regulation. This work constitutes a comprehensive resource for exploration of the molecular mechanisms of ovarian development and causes of female infertility.
2024-03-24 | GSE236860 | GEO
Project description:FOXL2 is a transcription factor essential for female fertility, expressed in somatic cells of the ovary, notably granulosa cells. In the mouse, Foxl2 deletion leads to partial sex reversal postnatally, with mutants developing dysgenic ovaries devoid of oocytes. However, deletion of the gene in 8-week-old females leads to granulosa to Sertoli cell transdifferentiation and gonadal sex reversal. We hypothesise that different outcomes of Foxl2 deletion in embryonic versus adult ovary may depend on a different role played by FOXL2 across ovarian development. Therefore, in this study, we take a multi-omics approach to characterise the dynamics of gene expression and chromatin accessibility changes in purified murine granulosa cells across key developmental stages (E14.5, 1 and 8 weeks). We coupled these analyses with genome wide identification of FOXL2 target genes and on-chromatin interacting partners by ChIP-SICAP to reconstruct the gene regulatory networks underpinned by this essential transcription factor and to discover novel players. We found that, in the embryonic ovary, FOXL2 interacts with factors important for early stages of gonadal development, such as GATA4 and WT1, whilst postnatally it interacts with factors regulating primordial follicle activation, such as NR5A2, and with factors regulating steroidogenesis including AR and ESR2. Integration of chromatin landscape dynamics with gene expression changes and FOXL2 binding sites analysis revealed that its critical role in ovarian cell fate maintenance goes beyond repression of the Sertoli-specific gene Sox9. Our chromatome analysis revealed also that FOXL2 interacts with several proteins involved in chromatin remodelling, DNA repair, splicing and gene repression. We identified a FOXL2 interactor with a role in primordial follicle activation, Ubiquitin specific protease 7 (USP7). We showed that conditional deletion of this gene in granulosa cells leads to a blockage of primordial follicle activation, impairs ovary development and leads to complete sterility. In summary, in this study we identified target genes dynamically regulated by FOXL2 across ovarian development including known and newly identified FOXL2 targets with a role in embryonic ovarian development and folliculogenesis, as well as cofactors that point towards additional roles played by FOXL2 besides transcriptional regulation. This work constitutes a comprehensive resource for exploration of the molecular mechanisms of ovarian development and causes of female infertility.
2024-03-24 | GSE236859 | GEO
Project description:It has previously been shown that FOXL2 and ESR1 cooperate to repress the testis-determining gene Sox9 in murine granulosa cells, and suggested that FOXL2/ESR1 cooperation may be central to granulosa cell differentiation (Uhlenhaut et al., 2009). However, no study has so far compared the DNA-binding of FOXL2 and ESR1 at the genomic level or analyzed the impact of FOXL2 on ESR1 binding to its regulatory elements. Here, we have analyzed and compared the genomic locations recognized by ESR1 and FOXL2 in E2-treated primary murine granulosa cells.
2015-07-01 | GSE62545 | GEO
Project description:FOXL2 is a transcription factor that plays a key role in sex determination, ovary development and maintenance. Mutations related to this gene have been described in syndromes involving premature ovarian failure and granulosa cell tumors. This kind of rare cancer (less than 5% of diagnosed ovarian cancers) has been causally associated with the FOXL2 c.402C>G, p.C134W mutation in 97% of the adult cases (AGCTs). In this study, we have used CRISPR technology to specifically eliminate the FOXL2 c.402C>G mutation in granulosa tumor cells. Our results indicate that this Cas9-mediated strategy allows the specific elimination of the mutation with no activity on the wild type allele. Granulosa cells depleted on FOXL2 c.402C>G show a reduced malignant phenotype. Specifically, we detect changes in cell proliferation, invasion, and cell death levels. In addition, we show that granulosa tumor cells become more susceptible to Dasatinib and Ketoconazole treatments when FOXL2 c.402C>G allele is eliminated. Our transcriptomic and proteomic analyses indicate that CRISPR-modified granulosa tumor cells significantly change their expression signature towards a wild type like phenotype. Finally, this expression signature has led us to discover new compounds with antiproliferative and proapoptotic effects on granulosa cell tumor cells. Our results demonstrate the potential of CRISPR for specifically targeting and eliminating a granulosa cell tumor-causing mutation, as well as its therapeutic potential for the treatment of this rare ovarian cancer.
2025-03-15 | PXD053682 | Pride
Project description:Primary ovarian insufficiency (POI) is characterized by accelerated loss of primordial follicles, which results in ovarian failure and concomitant menopause before age 40. 1-3% of females in the general population are diagnosed with POI and 80% of females with the inherited disease Classic Galactosemia (CG) will develop POI. CG is caused by mutations in the GALT gene encoding the enzyme galactose-1-phosphate uridylyltransferase. While dietary restriction of galactose is lifesaving in the neonatal period, the development of severe complications including POI is not mitigated. Additionally, the pattern of follicle loss have not been completely characterized. The chronic accumulation of aberrant metabolites such as galactose-1 phosphate and galactitol are the suspected culprits in the development of the sequelae, yet the mechanisms remain elusive. Our group uses a GalT gene-trapped mouse model to study the pathophysiology of CG. Recently, we showed that alterations in the Integrated Stress Response pathway occur in the ovaries of these mice, likely contributing to the POI phenotype. Using immunofluorescent staining in whole-ovary histology at progressive ages, we saw evidence of altered Integrated Stress Response activity in granulosa cells and primordial oocytes leading to accelerated primordial follicle growth, aberrant DNA damage repair, and increased cellular stress/death. RNA-sequencing of whole ovary revealed significant alterations in cholesterol/lipid metabolism and transcriptional regulation. Overall, our findings indicate abnormal stress response results in accelerated primordial follicle activation or “burnout,” which may explain the POI phenotype of fewer primordial follicles at later ages.
2023-02-01 | GSE196454 | GEO
Project description:Alternative splicing (AS) plays significant roles in fundamental biological activities. AS also are prevalent in the testis, but the regulations of alternative splicing in spermatogenesis is vague. Here, we report that Serine/arginine-rich splicing factor 1 (SRSF1), plays critical roles in alternative splicing and male reproduction. Male germ cell-specific deletion of Srsf1 led to complete infertility and abnormal spermatogenesis. We further demonstrated that Srsf1 is required for spermatogonial stem cell differentiation and mitotic-to-meiotic transition. Mechanistically, by combining RNA-seq data with LACE-seq data, we showed that SRSF1 regulatory networks have functions in spermatogenesis. Particularly, we found that SRSF1 affects the AS of Stra8 in a direct manner and Dazl, Dmc1, Mre11a, Syce2 and Rif1 in an indirect manner. Taken together, our findings demonstrate that SRSF1 has crucial functions in spermatogenesis and male fertility by regulating alternative splicing.
2024-03-31 | GSE226551 | GEO