The Molecular Genetic Jigsaw Puzzle of Vertebrate Sex Determination and Its Missing Pieces

Since the identification of SRY as the mammalian Y-chromosomal testis-determining gene a decade ago, more than a dozen additional genes essential for early gonadal development in mammals and other vertebrate classes have been identified. The location of these known pieces of the puzzle in the sex determination pathway, and how they interact, is briefly outlined. Two insights emerge: except for SRY, the same basic set of genes appears to operate during early gonadal development in all vertebrate classes, despite the difference in mechanisms; and vertebrate sex determination results from a complex network of regulatory interactions and not from a simple hierarchical cascade of gene actions. However, important pieces of the puzzle are still missing, such as the molecular nature of the sex switch in marsupials, monotremes and non-mammalian vertebrates; the target of SRY; the upstream regulators of SOX9; and the genes in the ovarian pathway. The enigma of SRY-positive XY gonadal dysgenesis females and SRY-negative XX males also indicates that the picture is still far from complete. Filling in these missing pieces is the challenge for the future.