Very strong expression of Dmrt1 protein in spermatogonia and more uniform expression in Sertoli cells. Image courtesy of David Zarkower.

Until recently, there seemed to be little in common between the sex-determining pathways among the animal phyla. However, there is now functional data to indicate that a transcription factor may be a regulator of male development that is shared by vertebrates, flies and worms.

So far, the only known similarities between genes involved in sexual development are between the mab-3 gene in Caernorhabditis elegans and the doublesex (dsx) gene of Drosophila melanogaster . Both genes encode transcriptional regulators that have a conserved zinc-finger-like DNA-binding domain, called the DM domain. The two proteins are also functionally related, as they are both required for differentiation of male-specific sense organs, regulation of yolk protein transcription and normal male mating behaviour. A DM-domain gene, Dmrt1, has been implicated in sexual development in vertebrates as well, a fact that prompted Raymond and colleagues to investigate whether it is required specifically for male development in the mouse.

A null allele of Dmrt1 was made by the targeted deletion of the DM domain (and the transcriptional start site). Male mice heterozygous for Dmrt1 appear normal, but homozygous males fail to maintain testis differentiation from postnatal day seven and onwards. The fact that Dmrt1−/− females develop into normal, fertile adults, supports the idea that Dmrt1 function is male specific.

Dmrt1 is necessary in the male gonad for the survival and differentiation of both somatic and germline cells. Germ cells are missing in the very small testes of the homozygous mutant mice, and the Sertoli cells, which provide nourishment to the early sperm cells, have abnormal cell morphology, overproliferate in early seminiferous tubules, and later die. Whether the germ-cell defect is cell autonomous, or results from the incorrect development of the Sertoli cells, is under investigation.

So far, no point mutations have been found in the human DMRT1 gene. But there is a similarity between the defects observed in the Dmrt1−/− male mice with those of human males carrying a distal deletion on 9p, where DMRT1 is located. This indicates that DMRT1 — alone or in combination with one or more tightly linked genes — might be required for testis development in humans.

SRY , the testis-determining gene, was discovered around ten years ago. When it emerged that SRY was exclusive to mammals, researchers began to look for its downstream targets in the hope that, unlike SRY, it would be common to all vertebrates. Perhaps the identification of Dmrt1 and this new data on its evolutionary conservation relating to a male-determining function in vertebrates, flies and worms, may mean that this hope has been realized.

Many developmental processes, such as body-axis establishment or segmentation, have a long-standing reputation for being evolutionarily conserved between phyla. The discovery that a certain protein signature (the DM domain) can help define male versus female development may mean that sex determination can now be added to this list.