Abstract
The elevated level of Steroidogenic Factor 1 (Nr5a1, Sf-1) expression in the male gonadal development pathway, post sex determination, implies a vital role in testis gonadal differentiation. In this study we generated Sertoli cell-specific Nr5a1 KO mice (SC-SF-1−/−) at E14.5, which coincides with testis development post sex determination, using the Amh-Cre mouse model. Analysis of SC-SF-1−/− (Sertoli cell specific Nr5a1 knockout) testes demonstrated apoptosis as early as E15. Further analysis revealed that SC-SF-1−/− gonads displayed lower MDM2 levels resulting in elevated TP53 levels, which we believe may lead to apoptosis of the Sertoli cell population, inferring the possibility that NR5A1 directly regulates MDM2 expression. By E15.5, the Sertoli cell and germ cell population declined in SC-SF-1−/− mice resulting in the disruption of seminiferous cords with limited cord structure remaining at E18.5. Due to the loss of Sertoli and germ cells, the testis weights of SC-SF-1−/− mice at 6-weeks were much reduced; however, SC-SF-1−/− seminal vesicles weights were comparable suggesting intact Leydig cell androgen production. We conclude that NR5A1 regulates the TP53 pathway during development, is essential for fetal Sertoli cell survival and controls the cell cycle of Sertoli cells during differentiation.
Highlights
Steroidogenic factor 1 (NR5A1), an orphan nuclear receptor was initially discovered as a transcription factor that regulated enzymes and cholesterol transport proteins in the steroidogenic pathway[1,2]
Adult Nr5a1fl/fl females carrying the Cre recombinase driven from the anti mullerian hormone (Amh) promoter are fertile
Our mating strategy included female Nr5a1fl/fl Amh-Cre mice mated to male Nr5a1fl/fl mice to generate SC-SF-1−/− male fetuses
Summary
Steroidogenic factor 1 (NR5A1), an orphan nuclear receptor was initially discovered as a transcription factor that regulated enzymes and cholesterol transport proteins in the steroidogenic pathway[1,2]. The Sertoli cell is the initial cell in the testis to functionally differentiate at E11.5 in mouse gonadal development following initiation of the male developmental pathway and Sry (sex-determining region Y) expression. The complete loss of Nr5a1 in null mutants results in gonadal dysgenesis in both males and females and this occurs in the bi-potential gonad after the gonadal and adrenal primordia separate, between E9.5 and E11.5 prior to sex determination[4]. In order to understand the developmental and cellular functions of NR5A1 in Sertoli cells of developing testis post sex determination, we developed a Sertoli cell specific knockout of Nr5a1 using the previously well-defined Amh-Cre mouse model. We have evidence that Nr5a1 ablation induced apoptosis is mediated through the MDM2/TP53 pathway This is the first study to demonstrate the role of NR5A1 as a possible survival and cell cycle checkpoint in the embryonic stages of male sexual development
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
