Nagahama, Y.; National Institute for Basic Biology, Okazaki, Japan: Howard Bern Lecture: The Plasticity of Fish Gender: An Evolutionary Basis for Sex Determination and
Differentiation in Vertebrates

In vertebrates, sex determination is a key event for the development of either testis or ovary. Among the vertebrates, fish exhibit a range of gonadal forms from gonochorism to several types of hermaphroditism. We showed that in fish DMRT1 and estrogens are critical for testicular and ovarian differentiation, respectively. The roles of these correlates were further ascertained by gene or hormonal blockade strategy. Naturally, some of the hermaphrodite species can change their sex. In addition, temperature seems to play a sex-determining role in some fish species. These features endorse that fish have the greatest sexual plasticity. Though higher vertebrates retain plasticity to some extent, the molecular cascades that lead to males and females seem to be relatively conserved. Conversely, sex determination in vertebrates seems diversified. Using positional cloning and shotgun sequencing, we isolated a strong candidate for sex-determining gene from medaka. This gene contains the highly conserved DM domain and is located on the Y chromosome, thus named DMY (DM-domain gene on the Y chromosome). DMY begins to express in Sertoli cells of XY gonads just prior to testicular differentiation. Loss- and gain-of-function studies have confirmed the role of DMY in male development, indicating that DMY is the sex-determining gene of medaka, the second one identified in any vertebrates. Interestingly, there is no sequence homology between two known sex-determining genes, SRY/Sry and DMY. Further, phylogenetic analysis indicated that DMY acts as the sex-determining gene only in a few species of medaka. Taken together, these findings suggest that despite some conserved mechanisms of gonadal sex differentiation, the top of this cascade, the sex-determining gene, exhibits extensive diversity among vertebrates.