Determinants of 4-repeat tau expression. Coordination between enhancing and inhibitory splicing sequences for exon 10 inclusion.
Mutations in the tau gene are pathogenic causing autosomal dominant frontotemporal dementia with Parkinsonism-chromosome 17 type (FTDP-17). Some mutations in tau exon 10 (E10) and immediately adjacent sequences cause disease by altering E10 splicing. To determine the mechanism of normal E10 splicing regulation and how FTDP-17 mutations alter splicing, mutational analysis of E10 was performed. The results show that E10 contains a complex array of both enhancer and inhibitor cis-acting elements that modulate usage of a weak 5' splice site. The 5' end of E10 contains a previously unrecognized multipartite exon splicing enhancer (ESE) composed of an SC35-like binding sequence, a purine-rich sequence, and an AC-rich element. Downstream of this ESE is a purine-rich exon splicing inhibitor. Intronic sequences immediately downstream of E10 also are inhibitory. The results support an alternative model in which I10 inhibitory sequences appear to function as a linear sequence. The cis-elements described are not redundant, and all appear required for normal E10 splicing. Results with double mutations demonstrate that the ESE and the intronic inhibitory element collaborate to regulate splicing. Thus splicing of tau E10 is regulated by a complex set of cis-acting elements that span nearly the entire exon and also include intronic sequences.
D'Souza
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Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle Division, Seattle, Washington 98108, USA.
Schellenberg
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D020121:5' Untranslated Regions / Q000235:genetics; D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D002886:Chromosomes, Human, Pair 17; D004742:Enhancer Elements, Genetic; D005091:Exons; D005914:Globins / Q000235:genetics; D006801:Humans; D007438:Introns; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009690:Nucleic Acid Conformation; D010300:Parkinson Disease / Q000235:genetics; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics*
D020121:5' Untranslated Regions; D016875:tau Proteins; D005914:Globins