The remarkable ubiquity of DM domain factors as regulators of sexual phenotype: ancestry or aptitude?

The DM domain is a cysteine-rich DNA-binding motif first recognized in proteins encoded by the Drosophila sex determination gene doublesex (Erdman and Burtis 1993; Zhu et al. 2000). As the name doublesex (dsx) suggests, this gene has functions in both sexes: Its transcripts undergo sex-specific alternative splicing, so that it can encode either a male-specific isoform, DSX, or a female-specific isoform, DSX (Baker and Wolfner 1988; Burtis and Baker 1989). These proteins have the same N-terminal DNA-binding domain, but different C termini that confer different regulatory properties on the two forms. The expression of DSX directs male development, and the expression of DSX directs female development, throughout most of the somatic tissues of the fruit fly. More recently, the same domain was discovered in nematodes, in the Caenorhabditis elegans male-abnormal gene mab-3, which has several biological functions similar to those of DSX (Shen and Hodgkin 1988; Raymond et al. 1998). Male worms mutant for mab-3 synthesize yolk proteins and show defects in male genital development similar to phenotypes seen in male flies that lack DSX. Underlining these similarities, it was found that ectopic expression of DSX (but not DSX) in C. elegans can partly rescue the mab-3 mutant phenotype (Raymond et al. 1998). This was the first example of a possible component shared between sex-determination mechanisms in different phyla, and the DM family was named on the basis of these two genes (dsx/mab-3). Searches for similar genes in other phyla were rewarded by the discovery of DMRT1 and related genes in vertebrates. DM family members have been increasingly implicated as playing important roles in sexual development, in a variety of different vertebrate and invertebrate species.