Trends in Genetics
ReviewMammalian sex reversal and intersexuality: deciphering the sex-determination cascade
Section snippets
AMH and the male sex
The basic constituents of the bipotential gonad consist of four cell types, the fate of which varies according to the genetic sex. Three are somatic cell types, supporting cell precursors, steroidogenic cells precursors and mesenchymal cells, derived from the genital ridge. The fourth cell type is derived from the germinal cell line, isolated early in the developing embryo (Fig. 1).
One central event of the male sex-determination pathway is the active regression of the Müllerian ducts in the
Regulation of AMH expression
To date, four proteins are known to interact with the AMH promoter and to regulate its expression, SF-1, WT1, SOX9 and GATA-4 (8., 9., 10., 11.), although information about the latter is scarce. In addition to their role in male sex determination, SF-1 and WT1 are also involved early in the development of the undifferentiated gonad from the urogenital ridge, as sketched in Fig. 1.
SF-1
SF-1 is a member of the orphan nuclear receptor family. It acts as a transcription factor to modulate transcription of several genes that encode proteins involved in steroidogenesis and male sex determination such as AMH, DAX-1 and StAR (for review, see Ref. 12). Recently, sequencing of the gene encoding SF-1 in a XY female patient revealed a 2-bp mutation that causes complete XY sex reversal, even in the heterozygote13. In mice, however, such a drastic phenotype (agenesis of gonads and adrenal
WT1
WT1 exerts its regulatory function on the promoter of the gene encoding AMH by interacting with SF-1 to modulate its binding to DNA. Mutations in WT1 are involved in four different human pathologies, each with characteristics of XY sex-reversal (reviewed in Ref. 14). These are Wilms’ tumour, the WAGR syndrome, Frasier Syndrome and Denys-Drash Syndrome. WT1 encompasses four zinc-finger domains. By ways of alternative splicing, alternative translation initiation and RNA editing, 16 different
SOX9
Another essential inducer of the AMH promoter is SOX9, discovered following the study of a rare bone pathology called campomelic dysplasia16., 17., 18.. Together with the bone disease, a mutant allele of SOX9 causes XY sex reversal in 75% of patients. SOX9 belongs to a family of proteins characterized by a conserved DNA-binding domain. This domain, termed the HMG box, is similar to the DNA-binding domain of SRY, shown to be involved in determination of the male sex in most mammalian species.
At the root of sex-determination: SRY and DAX-1
A major regulator of sex determination was discovered in 1994 with the finding that XY sex-reversal correlated with partial duplications of HSA Xp21. The minimal zone corresponding to the dose sensitive sex-reversal (DSS) locus was limited to 160 kb by Camerino and coworkers27 and the gene encoding DAX-1, a nuclear receptor expressed in the adult testis and adrenal glands, identified within this region. Binding of DAX-1 to DNA-hairpin loops in vitro suggests that this protein regulates
Other genes
Consistent with the hypothesis that many genes involved in mammalian sex determination remain unknown, most cases of XY sex reversal and all cases of XX males in the absence of SRY remain unsolved in humans. XX maleness in the absence of SRY is best explained by a negative-regulatory action of SRY. This hypothesis was developed in 1993 by McElreavey and coworkers39, who suggested that SRY inhibits a negative regulator of the male pathway, which itself acts on male-determining genes such as
Mammalian intersexuality
Intersexuality is a term that covers different biological states of sexual differentiation at any level, from the chromosomes to the brain. Inconsistencies between chromosomal and gonadal sex imply the occurrence of a specific pathology involving sex-determining genes (before the hormonal switch). This definition excludes well-documented diseases, such as freemartinism in many ruminant species (which occurs because of hormonal exchanges between male and female foetuses) or mutation of the genes
From horns to sex: history of the goat model
From the beginning of the 20th century, different species of domestic animals have had their performances and pedigrees registered in herdbooks. Using these, a fashionable or useful trait can be introduced into farm animals.
Probably about 100 years ago, a hornless buck was used to produce hornless progeny (Fig. 2). In farming, lack of horns is considered an advantage for many ruminant species, because horns can hurt other animals and farmers. Indeed, horns are often removed from young cattle
From P to PIS (Polled/Intersex Syndrome), towards the positional cloning of the gene
At the beginning of the 1990s, goat families were collected, taking advantage of the dominance of the absence of horns. Genome scanning located the gene to goat chromosome 1 at band 1q43 (Ref. 65). Subsequently, the mapping has been refined66., 67. and, by haplotype analysis, the mutation localized to one BAC which is currently being sequenced. No sex-reversing gene has been mapped in the homologous region in humans (3q23). However, a gene responsible for blepharophimosis ptosis epicanthus
Acknowledgements
The authors thank C. Cotinot, S. Chaffaux and B. Vigier for critical reading of the manuscript; B. Weiss for adding Table 1 to the web site; and C. Young for English corrections. A large amount of the goat work was carried out with grants from l'Institut National de la Recherche Agronomique: Activité Incitative Programmée ‘Sex autosomal determination in goats and pigs’ and Activité Incitative Programmée ‘Genome and function’.
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