MAMMALIAN SEX DETERMINATION - FROM GONADS TO BRAIN

In mammals, sex is determined by the Y chromosome, which encodes a tes tis-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 al l male sexual characteristics. In 1990, the sex-determining gene, TDF, was identified and termed SRY in humans (Sry in mice). It encodes a p rotein containing a high mobility group (HMG) motif, which confers the ability to bind and to bend DNA. Genetic evidence supporting SRY as T DF came from the observation of a male phenotype in XX mice transgenic for a small genomic fragment containing Sry, and from the study of XY sex-reversed individuals who harbor de novo mutations in the SRY codi ng sequence. Other non-Y-linked genes involved in sex determination we re subsequently found by genetic analysis of XY sex-reversed patients not explained by mutations in SRY. These genes are WT1, SF1, DAX1, and SOX9. A regulatory cascade hypothesis for mammalian sex determination , proposing that SRY represses a negative regulator of male developmen t, was recently supported by observation of mice that expressed a DAX1 transgene and developed as XY sex-reversed females. The role of some sex-determining genes, such as DAX1 and SF1, in the development of the entire reproductive axis, a functionally integrated endocrine axis, l eads to a new concept. Normal sexual development may result from the f unctional and developmental integration of a number of different genes that play roles in sex determination, sexual differentiation, and sex ual behavior. (C) 1998 Academic Press.