Sex and the Circuitry: Progress Toward a Systems-level Understanding of Vertebrate Sex Determination

In vertebrates, the gonad arises as a bipotential primordium that can differentiate as a testis or ovary. Cells are initially primed to adopt either fate by balanced antagonistic signaling pathways and transcription networks. Sexual fate is determined by activating the testis or ovarian pathway and repressing the alternative pathway. A complex, dynamic transcription network underlies this process, as approximately half the genome is being transcribed during this period, and many genes are expressed in a sexually dimorphic manner. This network is highly plastic; however, multiple lines of evidence suggest that many elements of the pathway converge on the stabilization or disruption of Sox9 expression. The single gene mutational approach has led to the identification of ∼30 additional genes involved in vertebrate sex determination. However, >50% of human disorders of sexual development (DSDs) are not explained by any of these genes, suggesting many critical elements of the system await discovery. Emerging technologies and genetic resources enable the investigation of the sex determination network on a global scale in the context of a variable genetic background or environmental influences. Using these new tools we can investigate how cells establish a bipotential state that is poised to adopt either sexual fate, and how they integrate multiple signaling and transcriptional inputs to drive a cell fate decision. Elucidating the genetic architecture underlying sex determination in model systems can lead to the identification of conserved modules correlated with phenotypic outcomes, and critical pressure points in the network that predict genes involved in DSDs in humans.