Several laboratories, including ours, use minigenes transfected into mammalian cells to study splicing regulation, which proved to be extremely useful to look at the mechanisms by which transcription controls alternative splicing. However, transfection experiments may be of poor physiological relevance because minigenes are chimeric constructs in which alternatively spliced regions are positioned at incorrect distances with respect to promoters. Furthermore, transfected minigenes act in a different gene environment and at high copy numbers. A more physiological approach to the coupling between transcription and splicing should necessarily study an endogenous gene in its natural environment. A first step in this direction is an observation obtained in Drosophila: flies carrying the C4 mutation show changes in the alternative splicing profile of the large ultrabithorax (Ubx) gene (de la Mata et al. 2003). The observed changes are consistent with a kinetic mechanism that allows more time for early splicing events. Most interestingly, Drosophila with the C4 allele in heterozygosis but wild type for both Ubx alleles show a mutant phenotype called "Ubx effect" that resembles the one seen in flies haploinsufficient for the Ubx protein (Greenleaf et al. 1980). It will be important to investigate to what extent this alteration in splicing isoform proportions is causative for the display of the Ubx-like phenotype.