Journal
JOURNAL OF NEUROCHEMISTRY
Volume 74, Issue 2, Pages 490-500Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1046/j.1471-4159.2000.740490.x
Keywords
microtubule-associated protein tau; expression pattern of regulated isoforms; microtubule binding domain; regulation of alternative splicing; frontotemporal dementia
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Funding
- NICHD NIH HHS [P01 HD05515] Funding Source: Medline
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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 in human tissue; by reconstituting naturally occurring FTDP mutants in the homologous context of exon 10, we show that the cis determinants of exon 10 splicing regulation include an exonic silencer within the exon, its 5' splice site, and the relative affinities of its flanking exons to it. By cotransfections in vivo, we demonstrate that several splicing regulators affect the ratio of tau isoforms by inhibiting exon 10 inclusion.
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