Alternative splicing of the Drosophila Dscam pre-mRNA is both temporally and spatially regulated

The Drosophila melanogaster Down syndrome cell adhesion molecule (Dscam) go ne encodes an axon guidance receptor that can express 38,016 different mRNA s by virtue of alternative splicing. The Dscam gene contains 95 alternative exons that are organized into four clusters of 12, 48, 33, and 2 exons eac h. Although numerous Dscam mRNA isoforms can be synthesized, it remains to be determined whether different Dscam isoforms are synthesized at different times in development or in different tissues. We have investigated the alt ernative splicing of the Dscam exon 4 cluster, which contains 12 mutually e xclusive alternative exons, and found that Dscam exon 4 alternative splicin g is developmentally regulated. The most highly regulated exon, 4.2, is inf requently used in early embryos but is the predominant exon 4 variant used in adults. Moreover, the developmental regulation of exon 4.2 alternative s plicing is conserved in D. yakuba. In addition, different adult tissues exp ress distinct collections of Dscam mRNA isoforms. Given the role of Dscam i n neural development, these results suggest that the regulation of alternat ive splicing plays an important role in determining the specificity of neur onal wiring. In addition, this work provides a framework to determine the m echanisms by which complex alternative splicing events are regulated.