SRY and the standoff in sex determination

Abstract

SRY was identified as the mammalian sex-determining gene more than 15 yr ago and has been extensively studied since. Although many of the pathways regulating sexual differentiation have been elucidated, direct downstream targets of SRY are still unclear, making a top down approach difficult. However, recent work has demonstrated that the fate of the gonad is actively contested by both male-promoting and female-promoting signals. Sox9 and Fgf9 push gonads towards testis differentiation. These two genes are opposed by Wnt4, and possibly RSPO1, which push gonads toward ovary differentiation. In this review, we will discuss the history of the field, current findings, and exciting new directions in vertebrate sex determination.

Figure 1

Reinforcing Loops that Propagate Testis or Ovary Fate The somatic precursors of the supporting cell lineage can become Sertoli cells or follicle cells dependent upon whether male- (FGF9) or female- (WNT4) promoting signals dominate the field. In a male environment, these cells become Sertoli cells, organize testis development, promote Leydig cell development, and regulate germ cells that arrest in G0/G1 [PGC (G1)]. In a female environment, the somatic precursors become follicle cell precursors. Their organization into follicle structures is dependent on meiotic germ cells [PGC (Mei)]. It is likely that reinforcing signals (dotted lines) exist between fetal follicle or Sertoli cells and theca or Leydig cells, respectively, although this has not yet been shown. Question marks denote putative interactions between Leydig or theca cells and germ cells.

Figure 2

Model of Opposed Signals in Mammalian Sex Determination A, In the bipotential gonad, male-promoting (SOX9 and FGF9) and female-promoting (WNT4 and possibly RSPO1) hold each other in check. B, The presence of SRY (XY) reinforces the positive feedback between SOX9 and FGF9, which then out-competes the female signals and drives testis differentiation. In the absence of SRY (XX), the female-promoting signals shut down the male loop and drive ovarian differentiation.