Gonadal Development

The commitment of the embryonic gonad towards the male or female fate is a sequential and complex developmental process. The sex-independent growth and development of the adrenogonadal primordium into the bipotential gonadal ridge is committed to the formation of testis in the presence of the SRY gene on the Y chromosome. SRY upregulates the expression of SOX9 that sets into motion a cascade of complex genetic interactions for the formation of male internal and external genitalia whilst repressing the formation of female genitalia. The initiation and maintenance of somatic sex of the gonad as either male or female is achieved by suppression of the alternate fate. However, at least in mice, the primary sex-determining decision is not final but is maintained in adulthood by a mutually antagonistic double-repressive pathway. In the human, any imbalance between these two antagonistic genetic and physiological pathways results in inappropriate gonad differentiation and function leading to disorders of sex development (DSD). Genetic analysis of individuals presenting with DSD and sex-reversed mice has revealed a number of sexually dimorphic genes that are involved in the formation of mammalian gonads, which are discussed in this chapter. Despite an increase in the knowledge of genes involved in mammalian sex determination, the molecular mechanisms remain by and large undetermined. The use of novel 'omics' technologies for analyzing a large number of patients with DSD, and careful assessment of the resulting datasets may result in the identification of novel genetic factors in human sex determination and lead to the development of novel ex vivo cellular models.