The Drosophila melanogaster sex determination hierarchy. The Drosophila sex determination hierarchy consists of a cascade of sex-specific alternatively spliced pre-mRNAs culminating in the production of sex-specific transcription factors encoded by doublesex (dsx) and fruitless P1 (fru P1). The primary determinate of sex is the X chromosome to autosomal chromosome (A) ratio. In females (X:A = 1), Sex Lethal (SXL) is produced and regulates the splicing of the pre-mRNA of transformer (tra), resulting in the production of TRA. TRA acts in conjunction with constitutively produced TRA-2, and regulates the alternative splicing of the pre-mRNAs of dsx and fru P1, leading to the production of the female-specific protein DSXF. In males (X:A = 0.5), SXL is not produced and dsx and fru P1 pre-mRNAs undergo default splicing, resulting in the production of the male sex-specific proteins DSXM and FRUM. In addition, in females SXL represses dosage compensation, the process by which transcription of genes on the single X chromosome in males is up-regulated to roughly equal that of the two X chromosomes in females.