Evolution of the neuron‐specific alternative splicing product of the c‐src proto‐oncogene

The observation of a slower migrating form of pp60^c‐src in neural tissue of chicken and mouse has recently been shown to be due to an alternative transcript form of the c‐src gene (Martinez et al.: Science 237:411–415, 1987; Levy et al.: Mol Cell Biol 7:4142–4145, 1987). An insertion of 18 basepairs between exons 3 and 4, presumed to be due to alternative splicing of a mini‐exon, gives rise to six amino acid residues not found in the non‐neuronal (termed fibroblastic) form of pp60^c‐src. We have addressed the question of the evolutionary origin of the c‐src neuronal insert and its functional significance regarding neural‐specific expression of the c‐src gene. To this end we have investigated whether the c‐src gene of a lower vertebrate (the teleost fish Xiphophorus) gives rise to a neural‐specific transcript in an analogous manner. We could show that the fish c‐src gene does encode for a “fibroblastic” and a “neuronal” form of transcript and that the neuronal transcript does indeed arise by way of alternative splicing of a mini‐exon. The miniexon is also 18 basepairs long and we could demonstrate directly that this exon lies within the intron separating exons 3 and 4. For comparative purposes we have examined whether the fish c‐yes gene, the member of the src gene family most closely related to c‐src, also encodes a neural tissue‐specific transcript. No evidence for a second transcript form in brain was obtained. This result suggests that the mini‐exon arose within the c‐src gene lineage sometime between the src/yes gene duplication event and the divergence of the evolutionary lineage giving rise to the teleost fish. Published genomic sequence of src‐related genes in Drosophila and our own results with Hydra demonstrate no intron in these species at the analogous location, consistent with first appearance of this mini‐exon sometime between 550 and 400 million years ago.