Reproduction (Cambridge, England) · 2025
Redundant functions and mechanisms of action of Slit1 and Slit2 in ovarian granulosa cells.
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Grudet Florine, Gusscott Samuel, Godin Philippe, Martinot Emmanuelle, Chédotal Alain, Brind'Amour Julie, Boerboom Derek
Аннотация
IN BRIEF: SLIT1 has recently been shown to regulate ovarian follicle development and female fertility. In this study, we elucidate SLIT1's intracellular signaling mechanisms and transcriptional targets and further show that it acts in a redundant manner with SLIT2 in granulosa cells.
ABSTRACT: Recent evidence has suggested that Slit1 regulates female fertility by acting on ovarian granulosa cells to antagonize gonadotropin-induced AKT signaling and luteinizing hormone (LH)-stimulated gene expression and to promote apoptosis and follicular atresia. We sought to further define the mechanisms of Slit1 action and verify its potential functional redundancy with Slit2 and Slit3. RNA-seq analyses of cultured granulosa cells treated with SLIT1 showed that SLIT1 upregulated 612 and downregulated 601 genes, which were determined to be involved in processes including cell metabolism, reproduction and development. Although Slit1 has been previously identified as a potential antagonist of LH action, RNA-seq analyses showed that exogenous SLIT1 antagonized the effect of LH on only 14.7% of its target genes. Analyses of gonadotropin-induced signaling cascades in granulosa cells showed that SLIT1 antagonizes follicle-stimulating hormone (FSH)- (but not LH-) induced FOXO1 phosphorylation. Analyses of mRNA levels of Slit1 target genes in granulosa cells treated with exogenous SLIT2 and SLIT3 showed SLIT2 (but not SLIT3) to be able to regulate most genes in a manner similar to SLIT1. Likewise, SLIT2 was able to antagonize FSH-stimulated AKT and FOXO1 signaling (and LH-stimulated AKT signaling), whereas SLIT3 could not. As for SLIT1, SLIT2 was also able to induce granulosa cells apoptosis in vitro. Loss of the SLIT receptor Robo1 did not inhibit the ability of SLIT1 or SLIT2 to antagonize AKT/FOXO1 signaling, suggesting that it does not function as their sole receptor. Together these findings suggest that Slit1 and Slit2 share common functions and mechanisms of action in the ovary.
ABSTRACT: Recent evidence has suggested that Slit1 regulates female fertility by acting on ovarian granulosa cells to antagonize gonadotropin-induced AKT signaling and luteinizing hormone (LH)-stimulated gene expression and to promote apoptosis and follicular atresia. We sought to further define the mechanisms of Slit1 action and verify its potential functional redundancy with Slit2 and Slit3. RNA-seq analyses of cultured granulosa cells treated with SLIT1 showed that SLIT1 upregulated 612 and downregulated 601 genes, which were determined to be involved in processes including cell metabolism, reproduction and development. Although Slit1 has been previously identified as a potential antagonist of LH action, RNA-seq analyses showed that exogenous SLIT1 antagonized the effect of LH on only 14.7% of its target genes. Analyses of gonadotropin-induced signaling cascades in granulosa cells showed that SLIT1 antagonizes follicle-stimulating hormone (FSH)- (but not LH-) induced FOXO1 phosphorylation. Analyses of mRNA levels of Slit1 target genes in granulosa cells treated with exogenous SLIT2 and SLIT3 showed SLIT2 (but not SLIT3) to be able to regulate most genes in a manner similar to SLIT1. Likewise, SLIT2 was able to antagonize FSH-stimulated AKT and FOXO1 signaling (and LH-stimulated AKT signaling), whereas SLIT3 could not. As for SLIT1, SLIT2 was also able to induce granulosa cells apoptosis in vitro. Loss of the SLIT receptor Robo1 did not inhibit the ability of SLIT1 or SLIT2 to antagonize AKT/FOXO1 signaling, suggesting that it does not function as their sole receptor. Together these findings suggest that Slit1 and Slit2 share common functions and mechanisms of action in the ovary.