SEX DETERMINING GENE-EXPRESSION DURING EMBRYOGENESIS

The Y-linked gene Sry acts during a critical period of gonadal differentiation to divert the normal or default pathway of gene activity that would otherwise lead to the development of ovaries into one that leads to the development of testes. It acts cell autonomously, probably within the cell lineage that gives rise to Sertoli cells in the testis or follicle cells in the ovary. The remaining cell types within the gonad, each of which has a developmental choice, then become fated to follow the testicular pathway. This process must depend on cell-cell interactions as Sry is not required within these other cell types for their differentiation. Subsequent male development of the animal as a whole is dependent on the production of testosterone and other factors by the testis. Sry encodes a DNA binding protein of the HMG box class, and presumably acts to regulate the expression of other genes which then confer cellular phenotype. However, rather than operating like other classes of transcription factor, it has been shown to induce a dramatic bend in its DNA binding sites, and may not directly affect transcription of target genes. Instead, it may permit other factors to interact, which in turn either activate or repress transcription. Sequence comparisons between Sry genes from various species suggest that the HMG box is the only functional part of the protein. This part is responsible for DNA binding, and both mouse and human SRY bind the same consensus sequence at high affinity in vitro. However, the human gene fails to cause female to male sex reversal in transgenic mice. Possible reasons for this are discussed. There is also much evidence, including transgenic data, to suggest that the level of expression of Sry is critical to its function. On top of this, the gene can only successfully induce testis differentiation if the correct cell-cell interactions occur within the developing gonad. Despite knowing the identity of the testis determining gene, we are therefore still a long way from understanding how it achieves its function.