Complex regulation of tau exon 10, whose missplicing causes frontotemporaldementia

Tau is a microtubule-associated protein whose transcript undergoes complex regulated splicing in the mammalian nervous system. Exon 10 of the gene is an alternatively spliced cassette that is adult-specific and that codes for a microtubule binding domain. Recently, mutations that affect splicing of exon 10 have been shown to cause inherited frontotemporal dementia (FTDP), In this study, we establish the endogenous expression patterns of exon 10 i n human tissue; by reconstituting naturally occurring FTDP mutants in the h omologous context of exon 10, we show that the cis determinants of exon 10 splicing regulation include an exonic silencer within the exon, its 5' spli ce site, and the relative affinities of its flanking exons to it. By cotran sfections in vivo, we demonstrate that several splicing regulators affect t he ratio of tau isoforms by inhibiting exon 10 inclusion.