Mammalian sex determination: a molecular drama

Abstract

Our knowledge of mammalian sex determination is based on two main areas of study. First, the characterization of the biological events that determine the sexual development of the individual, including patterns of gene expression, and second, the study of genetic mutations in humans and mice that lead to abnormal sexual phenotypes. In the search for molecular components of this process, the identification of genes in loci involved in human disease has been especially fruitful. Serendipity has also played a hand, where in several cases targeted mutations in mouse genes, being studied for other reasons, have led to unexpected sex reversal phenotypes. The collection of molecular candidates implicated in sex determination is now quite extensive. We are not able to fit all of these into simple pathways, where one gene acts on the next and so on in a linear fashion, as seems possible in the invertebrate model organisms, Caenorhabditis elegans and Drosophila. In part this is due to gaps in our knowledge, as we are clearly missing several key components, but it is looking increasingly likely that the system is much better described as a network of factors. In fact, the story so far is like some partly recovered script for a play. Thus some gene products are main characters with roles at several different stages, some act as a chorus, in a combinatorial fashion with others, whereas a few play a critical role in one scene and then disappear. The mechanism presumably evolved to be delicately poised to respond to the initial trigger to be male or female and then to amplify this decision while avoiding development of intersex phenotypes. It is therefore likely to be a system full of back-ups and functional redundancy. The complexity may also follow from the relatively late embryonic stage at which the decision is reached. This means that events occurring in one cell lineage have to be coordinated with others in the context of a developing organ and eventually the whole organism. We review here the story that is beginning to emerge, focusing mostly on the set of transcription factors that appear to play important leading and supporting roles. In mammals, the genetic sex of the embryo is established at fertilization with the inheritance of an X or Y chromosome from the father. However, the sex-determining process is set in motion only during the period of organogenesis when the gonads develop. The Y chromosome, through the testis-determining gene Sry, acts dominantly to trigger differentiation of testes from the indifferent gonads (or genital ridges) that would otherwise develop as ovaries (Gubbay et al. 1990; Sinclair et al. 1990). Sry is the only gene needed from the Y chromosome to establish male development, as shown by transgenic experiments where XX mice carrying the Sry gene develop as males (Koopman et al. 1991). Conversely, mutations in Sry can lead to relatively normal female development of XY mice and humans (Gubbay et al. 1992; Hawkins et al. 1992). Once the gonads begin to differentiate as testes or ovaries, they secrete factors, notably anti-Mullerian hormone (AMH, otherwise known as Mullerian-inhibiting substance, or MIS) and testosterone from the testes, which determine the sexual development of the rest of the embryo. There are many steps in this process that, when affected, will give rise to different degrees of sex reversal. The challenge has been to correlate the phenotype of affected individuals with the appropriate step and translate this into a molecular mechanism.