SRp54 (SFRS11), a regulator for tau exon 10 alternative splicing identified by an expression cloning strategy

被引:51
作者
Wu, Jane Y.
Kar, Amar
Kuo, David
Yu, Bing
Havlioglu, Necat
机构
[1] Northwestern Univ, Feinberg Sch Med, Ctr Med Genet, Dept Neurol,Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA
[2] Univ Sydney, Cent Clin Sch, Sydney, NSW 2006, Australia
[3] Univ Sydney, Royal Prince Alfred Hosp, Sydney, NSW 2006, Australia
[4] St Louis Univ, Dept Pathol, St Louis, MO 63103 USA
关键词
D O I
10.1128/MCB.00739-06
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The tau gene encodes a microtubule-associated protein that is critical for neuronal survival and function. Splicing defects in the human tau gene lead to frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), an autosomal dominant neurodegenerative disorder. Genetic mutations associated with FTDP-17 often affect tau exon 10 alternative splicing. To investigate mechanisms regulating tau exon 10 alternative splicing, we have developed a green fluorescent protein reporter for tau exon 10 skipping and an expression cloning strategy to identify splicing regulators. A role for SRp54 (also named SFRS11) as a tau exon 10 splicing repressor has been uncovered using this strategy. The overexpression of SRp54 suppresses tau exon 10 inclusion. RNA interference-mediated knock-down of SRp54 increases exon 10 inclusion. SRp54 interacts with a purine-rich element in exon 10 and antagonizes Tra2 beta, an SR-domain-containing protein that enhances exon 10 inclusion. Deletion of this exonic element eliminates the activity of SRp54 in suppressing exon 10 inclusion. Our data support a role of SRp54 in regulating tau exon 10 splicing. These experiments also establish a generally useful approach for identifying trans-acting regulators of alternative splicing by expression cloning.
引用
收藏
页码:6739 / 6747
页数:9
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