Tau exons 2 and 10, which are misregulated in neurodegenerative diseases, are partly regulated by silencers which bind a SRp30c.SRp55 complex that either recruits or antagonizes htra2beta1
Department of Cell Biology; Shriver Center
Medical Subject Headings
Animals; *Exons; Gene Expression Regulation; Hela Cells; Humans; Multiprotein Complexes; Mutation; Nerve Tissue Proteins; Neurodegenerative Diseases; Nuclear Proteins; Phosphoproteins; *RNA Splicing; RNA-Binding Proteins; Recombinant Fusion Proteins; *Silencer Elements, Transcriptional; tau Proteins
Tau is a microtubule-associated protein whose transcript undergoes complex regulated splicing in the mammalian nervous system. Exon 2 modulates the tau N-terminal domain, which interacts with the axonal membrane. Exon 10 codes for a microtubule binding domain, increasing the affinity of tau for microtubules. Both exons are excluded from fetal brain, but their default behavior is inclusion, suggesting that silencers are involved in their regulation. Exon 2 is significantly reduced in myotonic dystrophy type 1, whose symptoms include dementia. Mutations that affect exon 10 splicing cause frontotemporal dementia (FTDP). In this study, we investigated three regulators of exon 2 and 10 splicing: serine/arginine-rich (SR) proteins SRp55, SRp30c, and htra2beta1. The first two inhibit both exons; htra2beta1 inhibits exon 2 but activates exon 10. By deletion analysis, we identified splicing silencers located at the 5' end of each exon. Furthermore, we demonstrated that SRp30c and SRp55 bind to both silencers and to each other. In exon 2, htra2beta1 binds to the inhibitory heterodimer through its RS1 domain but not to exon 2, whereas in exon 10 the heterodimer may sterically interfere with htra2beta1 binding to a purine-rich enhancer (defined by FTDP mutation E10-Delta5 = Delta280K) directly downstream of the silencer. Increased exon 10 inclusion in FTDP mutant ENH (N279K) may arise from abolishing SRp30c binding. Also, htra2beta3, a naturally occurring variant of htra2beta1, no longer inhibits exon 2 splicing but can partially rescue splicing of exon 10 in FTDP mutation E10-Delta5. This work provides interesting insights into the splicing regulation of the tau gene.
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Citation: J Biol Chem. 2005 Apr 8;280(14):14230-9. Epub 2005 Feb 3. Link to article on publisher's site