Splicing of a regulated exon reveals additional complexity in the axonal microtubule-associated protein tau

Tau is a microtubule-associated protein whose transcript undergoes complex regulated splicing in the mammalian nervous system. Exon 6 of the gene is an alternatively spliced cassette whose expression pattern and splicing regulation had not been previously analyzed in the human. The expression profile of exon 6 is completely different from that of the better-analyzed exons 2, 3, 4A, and 10, implying the utilization of distinct regulatory factors. The default splicing behavior of the exon had demonstrated the existence of what were initially considered cryptic splice sites. However, analysis of the expression pattern of exon 6 suggests that these splice sites are utilized in certain human tissues and, if translated, would result in a radically altered tau protein. Lastly, expression of exon 6 minigene constructs in cells indicates that its flanking exons are involved in its inclusion and in the modulation of the ratio of its variants.