The Genetics and Biology of Vertebrate Sex Determination

that the HMG domain has other important roles that are The plan seemed so simple. Having discovered Sry, the yet to be discovered. mammalian testis-determining gene on the Y chromoWhat functions can be ascribed to the remainder of some, and shown that it is able to cause male sex deterthe SRY protein? Two schools of thought have emerged mination in chromosomally female transgenic mice, the on this issue. The first contends that the HMG domain hard work was surely done. A few more years of research is the only important part of the protein, based on the effort was expected to reveal how the SRY protein observation that it is the only part to show any appreciaworks, and to knock over all the other genes in the male ble conservation during evolution, and that almost all sex-determining pathway one by one, like dominoes, so human sex reversing mutations affect the HMG domain. yielding a complete picture of the molecular genetic The role of SRY might be simply to remodel chromatin pathway between switching on Sry and forming a testis. in order to facilitate gene expression. The opposing view Along the way, molecular markers of all the different cell holds that other parts of the protein are necessary for types in the developing testis would be generated, and interaction with accessory proteins in a transcriptional these would be used to provide a clear view of cellular complex. In vitro studies have identified a PDZ protein, events driving the morphogenesis of this complex orSIP1, that interacts with the C-terminal 7 amino acids gan. Thoughts could then turn, perhaps, to how ovaries of human SRY (Poulat et al., 1997), while transgenic develop from the same primordia, the genital ridges, in mouse studies suggest that mouse SRY is unable to the absence of Sry. function without its large and unique C-terminal glutaAt least, that was the plan 10 years ago. What has mine-rich repetitive domain (Bowles et al., 1999). Robin really been achieved in this time? A recent international Lovell-Badge (National Institute of Medical Research, symposium (The Genetics and Biology of Sex DetermiLondon, UK) described experiments in which a transnation, Novartis Foundation Symposium 244, London, gene containing the human SRY coding sequence sandMay 1–3, 2001) was devoted to just this question, examwiched between mouse Sry flanking sequences, was ining progress and problems in understanding the gefound to promote male development in XX mice. Since netics, biology, and evolution of sex determination in the mouse and human proteins have only the HMG dovertebrates. In summary, a great deal of progress has main in common, these results are consistent with the been made, yet some of the most fundamental issues idea that only the HMG domain is important, although are still unresolved. further transgenic mouse studies are required to test