Abstract
Alternative pre-mRNA splicing is a powerful mechanism of gene expression control in eukaryotic cells that can influence cell function, cellular differentiation, and development. In some instances, as exemplified by the sex-specific regulation of transformer splicing by the Sex-lethal (Sxl) gene product in Drosophila, it may be used as an on/off switch of gene expression, mimicking transcriptional control (1). Other examples, like the cell-specific splicing of the calcitonin/CGRP pre-mRNA (2) or the sex-specific splicing of the Drosophila doublesex pre-mRNA (1), illustrate that alternative splicing provides an economical way to switch between mutually exclusive gene functions in a cell- or stage-specific manner. Its extraordinary versatility in the regulation of gene function is amply demonstrated by recent findings suggesting that electrical tuning of the hair cells in the inner ear of the chick is accomplished in part through variations in the splicing of the cSlo primary transcript, which has the potential of generating at least 576 different proteins (reviewed in Ref. 3). Alternative splicing can thus provide a means to store, within a single gene, finely tuned information gradients that can be distributed in a spatially regulated manner. The latter example also illustrates that in many instances there may be a need for tight control of alternative splicing patterns, which in turn may require complex mechanisms of regulation.
How are alternative splicing patterns controlled, and what are the trans-acting factors involved? Although the identification of the Drosophila products of the sex-determination genes Sex-lethal, transformer, and transformer 2 as splicing regulators was made possible by the unique power of Drosophila genetics, corresponding efforts to identify mammalian splicing regulators has so far had to rely on biochemical approaches. As a result of the complexity generally observed in alternative splicing patterns, it has been difficult to identify mammalian factors involved in the cell- or stage-specific control of single splicing events.