A regulatory cascade hypothesis for mammalian sex determination: SRY represses a negative regulator of male development.

Abstract

The mammalian Y chromosome carries the SRY gene, which determines testis formation. Here we review data on individuals who are XX but exhibit male characteristics: some have SRY; others do not. We have analyzed three families containing more than one such individual and show that these individuals lack SRY. Pedigree analysis leads to the hypothesis that they carry recessive mutations (in a gene termed Z) that allow expression of male characteristics. We propose that wild-type Z product is a negative regulator ofmale sex determination and is functional in wild-type females. In males, SRY product represses or otherwise negatively regulates Z and thereby allows male sex determination. This hypothesis can also explain other types of sex reversal in mammals, in particular, XY females containing SRY. Some of these individuals may have mutations at the Z locus rendering them insensitive to SRY. Recessive mutations (such as the polled mutation ofgoats) leading to sex reversal are known in a variety of animals and might be used to map and ultimately clone the human Z gene.In mammals, male sex determination is controlled by the presence ofthe Y chromosome, which carries a gene encoding the testis-determining factor (TDF) on its short arm (1, 2). The current hypothesis for TDF action is that its product induces the testis-determination pathway, resulting ultimately in a male phenotype (1,(3)(4)(5)(6). Recently, the testis-determining factor gene has been isolated and named SR Y for sexdetermining region, Y chromosome (7). Genetic evidence to equate SRY and TDF comes from the study of XY sexreversed females who harbor de novo mutations in the SR Y open reading frame (ORF). The association of a de novo mutation in the SR Y ORF with a sex-reversed phenotype is consistent with SR Ybeing TDF (8-12). Further support for the role of SRY as the primary testis-determining factor comes from the observation that XX mice carrying the murine equivalent of SRY as a transgene develop as males (13).Mutations that cause sex reversal have proved to be important for identifying genes involved in sex determination in Drosophila, nematodes, and mice (5, 14 XX males with genital ambiguities: Sporadic andfamilial cases. Thirty-eight sporadic cases of XX males were analyzed for the presence of Y material (21). They were detected at birth because of external genital ambiguities, such as hypospadias (failure of urethra to close on the underside of the penis), micropenis, or hyperclitoridy. In all 38 cases, gonadal biopsy revealed the presence of bilateral testis. We also analyzed a familial case (family A) in which two children were XX males with ambiguities such as posterior hypospadias. As shown in Fig. 1, they have two normal brothers and five normal sisters. Both parents are normal; they are related by a first-cousin marriage.46,XX true hermaphrodites: Sporadic and familial cases. Thirty-four sporadic cases have been analyzed; the majority have been previously published (21,22). They all carried internal or external genital ambiguities ...

Human SRY inhibits β-catenin-mediated transcription

“…One such measure could be the function of SRY as an "anti-ovary" gene to antagonize Wnt/β-catenin signaling allowing normal testis differentiation in the XY gonad. A similar but more general hypothesis was put forward by McElreavey et al (McElreavey et al, 1993), who suggested that SRY may repress a negative regulator, termed "Z" of male development. Our data identifies a repressive "anti-ovary" function of SRY: the inhibition of the female-specific Wnt/β-catenin signaling pathway, where the Wnt/β-catenin signaling pathway is the negative regulator "Z" (Figure 7).…”

“…This observation also indicates that RSPO1 may have two complementary functions, a "pro-ovary" function in initiating female gonadal development and an "anti-testis" function in inhibiting the male gonadal development pathway (Chassot et al, 2008). Several years ago, the analysis of a number of XX male patients led McElreavey et al to propose that an unidentified female "Z" gene was involved in repressing male gonadal development and that SRY was actively involved in the repression of the "Z" gene in the XY gonad, allowing testis development to proceed (McElreavey et al, 1993). Therefore, it is possible that RSPO1 or downstream effectors of the RSPO1 signaling pathway could assume the function of the "Z" repressor gene (Bernard and Harley, 2007).…”

Clinical, cytogenetic, and molecular analysis with 46,XX male sex reversal syndrome: case reports

“…Molecular genetics analyses have demonstrated that approximately 90 % of these patients carry a variable amount of Y material due to a Y-to-X interchange caused by an illegitimate recombination during paternal meiosis [13][14][15]. There was a report of an XX male caused by a translocation of an SRY gene fragment from the Y chromosome to an autosome [16].…”

FOXL2 versus SOX9: A lifelong “battle of the sexes”

“…Absence of Z would lead to SOX9 expression, testis development, and XX sex reversal. [14] We will come back to this idea below (Fig. 1).…”