From Enrico Sertoli to freemartinism: the many phases of the master testis-determining cell†

Abstract

Sertoli cells, first identified in the adult testis by Enrico Sertoli in the mid-nineteenth century, are known for their role in fostering male germ cell differentiation and production of mature sperm. It was not until the late twentieth century with the discovery of the testis-determining gene SRY that Sertoli cells' new function as the master regulator of testis formation and maleness was unveiled. Fetal Sertoli cells facilitate the establishment of seminiferous cords, induce appearance of androgen-producing Leydig cells, and cause regression of the female reproductive tracts. Originally thought be a terminally differentiated cell type, adult Sertoli cells, at least in the mouse, retain their plasticity and ability to transdifferentiate into the ovarian counterpart, granulosa cells. In this review, we capture the many phases of Sertoli cell differentiation from their fate specification in fetal life to fate maintenance in adulthood. We also introduce the discovery of a new phase of fetal Sertoli cell differentiation via autocrine/paracrine factors with the freemartin characteristics. There remains much to learn about this intriguing cell type that lay the foundation for the maleness.

Keywords: freemartin; sertoli cells; sex determination; testis.

Figure 1

Different phases of Sertoli cell differentiation. (A) Specification of Sertoli cell fate is induced cell-autonomously by transcription factor SRY and its downstream effectors SOX8/9. The pre-Sertoli cell population is further expanded and secured via the action of FGF9 and PGD2. (B) Once the identity of fetal Sertoli cells is established, Sertoli cells produce AMH, activin B, and other unknown factors, which serve as autocrine/paracrine factors to maintain the Sertoli cell identity. (C) In adult Sertoli cells, transcription factors SOX8/9 and DMRT1 are required for the maintenance of Sertoli cell identity. This figure was created with BioRender.com.