Mammalian Sex Determination: From Gonads to Brain

Abstract

In mammals, sex is determined by the Y chromosome, which encodes a testis-determining factor (TDF). This factor causes the undifferentiated embryonic gonads to develop as testes rather than ovaries. The testes subsequently produce the male sex hormones that are responsible for all male sexual characteristics. In 1990, the sex-determining gene, TDF, was identified and termedSRYin humans (Sryin mice). It encodes a protein containing a high mobility group (HMG) motif, which confers the ability to bind and to bend DNA. Genetic evidence supportingSRYas TDF came from the observation of a male phenotype in XX mice transgenic for a small genomic fragment containingSry,and from the study of XY sex-reversed individuals who harborde novomutations in theSRYcoding sequence. Other non-Y-linked genes involved in sex determination were subsequently found by genetic analysis of XY sex-reversed patients not explained by mutations in SRY. These genes areWT1, SF1, DAX1,andSOX9.A regulatory cascade hypothesis for mammalian sex determination, proposing thatSRYrepresses a negative regulator of male development, was recently supported by observation of mice that expressed aDAX1transgene and developed as XY sex-reversed females. The role of some sex-determining genes, such asDAX1andSF1,in the development of the entire reproductive axis, a functionally integrated endocrine axis, leads to a new concept. Normal sexual development may result from the functional and developmental integration of a number of different genes that play roles in sex determination, sexual differentiation, and sexual behavior.