SRp54 (SFRS11), a Regulator for tau Exon 10 Alternative Splicing Identified by an Expression Cloning Strategy

doi:10.1128/MCB.00739-06

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SRp54 (SFRS11), a Regulator for tau Exon 10 Alternative Splicing Identified by an Expression Cloning Strategy

Jane Y. Wu,¹^* Amar Kar,¹ David Kuo,¹ Bing Yu,¹^,2 and Necat Havlioglu³

Northwestern University Feinberg School of Medicine, Department of Neurology, Lurie Comprehensive Cancer Center, Center for Genetic Medicine, 303 E. Superior St., Chicago, Illinois 60611,¹ Central Clinical School and Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia,² Department of Pathology, Saint Louis University, St. Louis, Missouri³

Received 28 April 2006/ Returned for modification 2 June 2006/ Accepted 27 June 2006

The tau gene encodes a microtubule-associated protein that iscritical for neuronal survival and function. Splicing defectsin the human tau gene lead to frontotemporal dementia with Parkinsonismlinked to chromosome 17 (FTDP-17), an autosomal dominant neurodegenerativedisorder. Genetic mutations associated with FTDP-17 often affecttau exon 10 alternative splicing. To investigate mechanismsregulating tau exon 10 alternative splicing, we have developeda green fluorescent protein reporter for tau exon 10 skippingand an expression cloning strategy to identify splicing regulators.A role for SRp54 (also named SFRS11) as a tau exon 10 splicingrepressor has been uncovered using this strategy. The overexpressionof SRp54 suppresses tau exon 10 inclusion. RNA interference-mediatedknock-down of SRp54 increases exon 10 inclusion. SRp54 interactswith a purine-rich element in exon 10 and antagonizes Tra2ß,an SR-domain-containing protein that enhances exon 10 inclusion.Deletion of this exonic element eliminates the activity of SRp54in suppressing exon 10 inclusion. Our data support a role ofSRp54 in regulating tau exon 10 splicing. These experimentsalso establish a generally useful approach for identifying trans-actingregulators of alternative splicing by expression cloning.

* Corresponding author. Mailing address: Northwestern University Feinberg School of Medicine, Center for Genetic Medicine, 303 E. Superior St., Lurie 6-117, Chicago, IL 60611. Phone: (312) 503-0684. Fax: (312) 503-5603. E-mail: jane-wu{at}northwestern.edu.

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