T 1626 Alternative splicing controls sex determination in Drosophila

antigen, whereas the use of the other 5' splice site (which is farther downstream) produces an mRNA encoding the small t antigen.

A protein called splicing factor 2 (SF2) enhances the production of mRNA encoding the small t antigen (see Figure 16.25). Splicing factor 2 has two binding domains: one is an RNA-binding region and the other has alternating serine and arginine amino acids. These two domains are typical of SR proteins, which often play a role in regulating splicing. Splicing factor 2 stimulates the binding of U1 snRNP to the 5' splice site, one of the earliest steps in RNA splicing (see Chapter 14). The precise mechanism by which SR proteins influence the choice of splice sites is poorly understood. One model suggests that SF2 and other SR proteins bind to specific splice sites on mRNA and stimulate the attachment of snRNPs, which then commit the site to splicing.

Another example of alternative mRNA splicing that regulates the expression of genes controls whether a fruit fly develops as male or female. Sex differentiation in Drosophila arises from a cascade of gene regulation (Figure 16.26). When the ratio of X chromosomes to the number of haploid sets of autosomes (the X; A ratio; see Chapter 4) is 1, a female-specific promoter is activated early in development and stimulates the transcription of the sex-lethal (Sxl) gene. The protein encoded by Sxl regulates the splicing of the pre-mRNA transcribed from another gene called transformer (tra). The splicing of tra pre-mRNA results in the production of Tra protein. Together with another protein (Tra-2), Tra stimulates the female-specific splicing of pre-mRNA from yet another gene called doublesex (dsx). This event produces a female-specific Dsx protein, which causes the embryo to develop female characteristics.

In male embryos, which have an X;A ratio of 0.5 (see Figure 16.26), the promoter that transcribes the Sxl gene in females is inactive; so no Sxl protein is produced. In the absence of Sxl protein, Tra pre-mRNA is spliced at a different 3' splice site to produce a nonfunctional form of Tra protein (Figure 16.27). In turn, the presence of this nonfunctional Tra in males causes Dsx pre-mRNAs to be spliced differently (see Figure 16.26), and a male-specific Dsx protein is produced. This event causes the development of male-specific traits.

In summary, the Tra, Tra-2, and Sxl proteins regulate alternative splicing that produces male and female pheno-types in Drosophila. Exactly how these proteins regulate alternative splicing is not yet known, but it's possible that the Sxl protein (produced only in females) may block the upstream splice site on the tra pre-mRNA. This blockage would force the spliceosome to use the downstream 3' splice site, which causes the production of Tra protein and eventually results in female traits (see Figure 16.27). __

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