Foxo1 directs the transdifferentiation of mouse Sertoli cells into granulosa-like cells

Sertoli and granulosa cells, the initial differentiated somatic cells in bipotential gonads, play crucial roles in directing male and female gonad development, respectively. The transcription factor Foxo1 is involved in diverse cellular processes, and its expression in gonadal somatic cells is sex-dependent. While Foxo1 is abundantly expressed in ovarian granulosa cells, it is notably absent in testicular Sertoli cells. Nevertheless, its function in gonadal somatic cell differentiation remains elusive. In this study, we find that ectopic expression of Foxo1 in Sertoli cells leads to defects in testes development. Further study uncovers that the ectopic expression of Foxo1 induces the abundant expression of Foxl2 in Sertoli cells, along with the upregulation of other female-specific genes. In contrast, the expression of male-specific genes is reduced. Mechanistic studies indicate that Foxo1 directly binds to the promoter region of Foxl2, inducing its expression. Our findings highlight that Foxo1 serves as a key regulator for the lineage maintenance of ovarian granulosa cells. This study contributes valuable insights into understanding the regulatory mechanisms governing the lineage maintenance of gonadal somatic cells.