Figure 7–57 Alternative splicing of RNA transcripts of the Drosophila Dscam gene. DSCAM proteins have several different functions. in cells of the fly immune system, they mediate the phagocytosis of bacterial pathogens. in cells of the nervous system, DSCAM proteins are needed for proper wiring of neurons. the final mrnA contains 24 exons, four of which (denoted A, B, C, and D) are present in the Dscam gene as arrays of alternative exons. each rnA contains 1 of 12 alternatives for exon A (red), 1 of 48 alternatives for exon B (green), 1 of 33 alternatives for exon C (blue), and 1 of 2 alternatives for exon D (yellow). this figure shows only one of the many possible splicing patterns (indicated by the red line and by the mature mrnA below it). each variant DSCAM protein would fold into roughly the same structure (predominantly a series of extracellular immunoglobulin-like domains linked to a membrane-spanning region; see figure 24–48), but the amino acid sequence of the domains vary according to the splicing pattern. the diversity of DSCAM variants contributes to the plasticity of the immune system as well as the formation of complex neural circuits; we take up the specific role of the DSCAM variants in more detail when we describe the development of the nervous system in Chapter 21. (Adapted from D.l. Black, Cell 103:367–370, 2000. with permission from elsevier.) but very common in flies. Budding yeast has ≈6200 genes, only about 300 of which are subject to splicing, and nearly all of these have only a single intron. To say that flies have only 2–3 times as many genes as yeasts greatly underestimates the difference in complexity of these two genomes.
In some cases, alternative RNA splicing occurs because there is an intron sequence ambiguity: the standard spliceosome mechanism for removing intron sequences (discussed in Chapter 6) is unable to distinguish clearly between two or more alternative pairings of 5ʹ and 3ʹ splice sites, so that different choices are made by chance on different individual transcripts. Where such constitutive alternative splicing occurs, several versions of the protein encoded by the gene are made in all cells in which the gene is expressed.
In many cases, however, alternative RNA splicing is regulated. In the simplest examples, regulated splicing is used to switch from the production of a nonfunctional protein to the production of a functional one (or the other way around). The transposase that catalyzes the transposition of the Drosophila P element, for example, is produced in a functional form in germ cells and a nonfunctional form in somatic cells of the fly, allowing the P element to spread throughout the genome of the fly without causing damage in somatic cells (see Figure 5–61). The difference in transposon activity has been traced to the presence of an intron sequence in the transposase RNA that is removed only in germ cells.
In addition to enabling switching from the production of a functional protein to the production of a nonfunctional one (or vice versa), the regulation of RNA splicing can generate different versions of a protein in different cell types, according to the needs of the cell. Tropomyosin, for example, is produced in specialized forms in different types of cells (see Figure 6–26). Cell-type-specific forms of many other proteins are produced in the same way.
RNA splicing can be regulated either negatively, by a regulatory molecule that prevents the splicing machinery from gaining access to a particular splice site on the RNA, or positively, by a regulatory molecule that helps direct the splicing machinery to an otherwise overlooked splice site (Figure 7–58).