Sex Maintenance in Mammals

Abstract

The crucial event in mammalian sexual differentiation occurs at the embryonic stage of sex determination, when the bipotential gonads differentiate as either testes or ovaries, according to the sex chromosome constitution of the embryo, XY or XX, respectively. Once differentiated, testes produce sexual hormones that induce the subsequent differentiation of the male reproductive tract. On the other hand, the lack of masculinizing hormones in XX embryos permits the formation of the female reproductive tract. It was long assumed that once the gonad is differentiated, this developmental decision is irreversible. However, several findings in the last decade have shown that this is not the case and that a continuous sex maintenance is needed. Deletion of Foxl2 in the adult ovary lead to ovary-to-testis transdifferentiation and deletion of either Dmrt1 or Sox9/Sox8 in the adult testis induces the opposite process. In both cases, mutant gonads were genetically reprogrammed, showing that both the male program in ovaries and the female program in testes must be actively repressed throughout the individual's life. In addition to these transcription factors, other genes and molecular pathways have also been shown to be involved in this antagonism. The aim of this review is to provide an overview of the genetic basis of sex maintenance once the gonad is already differentiated.

Keywords: gonadal cells transdifferentiation; gonadal genetic reprograming; mammalian sex maintenance; ovary differentiation; sex determination; testis differentiation.

Figure 1

Gonadal cell-fate during gonad differentiation in mice. Prior to the sex determination stage, the bipotential gonad is composed of undifferentiated somatic cells (light pink) and germ cells (light blue). Sex differentiation starts with the specification (commitment) of the supporting cell progenitors to differentiate as either Sertoli cells in the testis or granulosa cells in the ovary. At the sex determination stage in XY individuals, the testis determining gene, SRY, starts to be expressed in the progenitors of the Sertoli cells (pre-Sertoli cells), leading to SOX9 upregulation and Sertoli cell specification. Subsequently, pre-Sertoli cells undergo a mesenchymal to epithelial transition and differentiate into Sertoli cells that form the testis cords enclosing the XY germ cells. Sertoli cells follow a male-specific genetic program expressing genes such as SOX9, SOX8, DMRT1, and AMH promote the differentiation of the steroidogenic Leydig cells and prevent XY germ cells from meiosis entry. In mice, all these events are completed within 24–48 h after sex determination. In the adult testis, cords become seminiferous tubules with lumen and germ cells at different pre-meiotic, meiotic, and post-meiotic stages including spermatogonia, spermatocytes, spermatids, and sperm. In XX gonads, the male pathway is not activated at the sex determination stage due to the lack of SRY and the WNT signaling genes, WNT4 and RSPO1, are upregulated in pre-granulosa cells. In the mouse, ovary differentiation is delayed with respect to testis differentiation and starts with meiosis initiation by XX germ cells, concomitant with the expression of further ovarian genes and pathways including FOXL2, TGFβ, and FST. Folliculogenesis is completed after birth, when germ cells are surrounded by a layer of granulosa cells. Follicle maturation in the mouse ovary begins a few days after birth including the proliferation of granulosa cells and the formation of an outer layer of steroidogenic theca cells.

Figure 2

Current model for the maintenance of sex-specific supporting cell fates in adult gonads. In Sertoli cells, SOX9/8 establish a feed-forward regulatory loop with DMRT1, necessary for the maintenance of the male-specific program and for preventing the expression of ovary-promoting genes including FOXL2. DMRT1 inhibits RA signaling, which induces the expression of ovarian genes. In granulosa cells, FOXL2 interacts with ESR1/2 and probably with other genes and molecular pathways including WNT, TGFβ, FST, LATS1/2, FOXO1/3, and RUNX1 to maintain the female-specific program. FOXL2 together with ESR1/2 negatively regulates SOX9/8 and/or DMRT1. Male- and female-promoting genes are in blue and red, respectively. Blue and red lines represent an action exerted by male- and female-promoting genes, respectively. Positive regulation is indicated by arrows. Negative regulation is indicated by perpendicular lines.