title: 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 termed SRY in humans (Sry in mice). It encodes a protein containing a high mobility group (HMG) motif, which confers the ability to bind and to bend DNA. Genetic evidence supporting SRY as TDF 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 coding 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 are WT1, SF1, DAX1, and SOX9. A regulatory cascade hypothesis for mammalian sex determination, proposing that SRY represses a negative regulator of male development, 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, 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.
authors.affiliation: Department of Human Genetics, UCLA School of Medicine and UCLA Children's Hospital, Los Angeles, California, 90095-1752, USA.
authors.forename: E
authors.initials: E
authors.lastname: Vilain
authors.forename: E R
authors.initials: ER
authors.lastname: McCabe
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000502:physiology; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D012734:Disorders of Sex Development; D005260:Female; D006066:Gonads / Q000254:growth & development / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000502:physiology; D012097:Repressor Proteins; D019849:Sex Determination Processes; D012733:Sex Differentiation / Q000235:genetics / Q000502:physiology; D051876:Sex-Determining Region Y Protein; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D014960:X Chromosome / Q000235:genetics; D014998:Y Chromosome / Q000235:genetics
chemical_list: D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; C539965:NR0B1 protein, human; C539966:Nr0b1 protein, mouse; D009687:Nuclear Proteins; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; C497745:SRY protein, human; D051876:Sex-Determining Region Y Protein; C497746:Sry protein, mouse; D014157:Transcription Factors