Alternated splicing of tau in development and neurodegenerating disorders with dementia.

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Tau is one of the microtubule-associated proteins (MAPs) that play a role in promoting the polymerization and stabilization of neuronal microtubules and is involved in both the maintenance of the neuronal cytoskeleton and axonal transport. Human tau is encoded by a single gene (TAU) on chromosome 17 from which six isoforms are produced in the adult brain by alternative splicing of exons 2, 3 and 10. Tau exon 10 (E10) encodes the second microtubule-binding domain, and alternative splicing of this exon results in isoforms with three (E10-) or four (E10+) microtubule-binding domains referred to as three-repeat tau (3R-tau) and four-repeat tau (4R-tau), respectively. 4R-tau binds microtubules more avidly than 3R-tau due to its additional microtubule-binding domain encoded with E10. In human brains, only 3R-tau is expressed in the fetal stage while both 3R-tau and 4R-tau are expressed in a ratio of approximately 1:1 in the adult stage. In contrast, rodent brains express only 3R-tau in fetal and neonatal stages and only 4R-tau in the adult stage. Some mutations of the TAU gene found in frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) have been shown to affect alternative splicing of E10 and to thereby increase or decrease the ratio of 3R-tau to 4R-tau. Thus, as splicing of mouse E10 is different from human E10, the comparison of two genomic sequences is expected to provide a useful information. Genomic fragments were isolated from mouse genome libraries and compared with human sequence. We identified a new element in mouse intron 10 (I10) to suppress E10 splicing, which was located just after the stem-loop region previously proposed in human sequence and found to potentially form another stem-loop. Human I10 with a mutation (+29G to A) causing a decreased E10 splicing was also predicted to form similar double stem-loop, suggesting that this element is universally involved in regulation of E10 splicing.