tau Exon 10 expression involves a bipartite intron 10 regulatory sequence and weak 5' and 3' splice sites.
tau mutations that deregulate alternative exon 10 (E10) splicing cause frontotemporal dementia with parkinsonism chromosome 17-type by several mechanisms. Previously we showed that E10 splicing involved exon splicing enhancer sequences at the 5' and 3' ends of E10, an exon splicing silencer, a weak 5' splice site, and an intron splicing silencer (ISS) within intron 10 (I10). Here, we identify additional regulatory sequences in I10 using both non-neuronal and neuronal cells. The ISS sequence extends from I10 nucleotides 11-18, which is sufficient to inhibit use of a weakened 5' splice site of a heterologous exon. Furthermore, ISS function is location-independent but requires proximity to a weak 5' splice site. Thus, the ISS functions as a linear sequence. A new cis-acting element, the intron splicing modulator (ISM), was identified immediately downstream of the ISS at I10 positions 19-26. The ISM and ISS form a bipartite regulatory element, within which the ISM functions when the ISS is present, mitigating E10 repression by the ISS. Additionally, the 3' splice site of E10 is weak and requires exon splicing enhancer elements for efficient E10 inclusion. Thus far, tau FTDP-17 splicing mutations affect six predicted cis-regulatory sequences.
D'Souza
Ian
I
Division of Gerontology, Department of Medicine, University of Washington and Geriatric Research Education and Clinical Center, Veterans Affairs Puget Siund Health Care System, Seattle Division, USA.
Schellenberg
Gerard D
GD
D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D005091:Exons; D006801:Humans; D007438:Introns; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D009690:Nucleic Acid Conformation; D022821:RNA Splice Sites / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016875:tau Proteins / Q000235:genetics*
D022821:RNA Splice Sites; D016875:tau Proteins