Human Molecular Genetics Advance Access published online on August 28, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm233
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Expression, localization and Tau Exon 10 splicing activity of the brain RNA-binding protein TNRC4
1 MRC Centre for Neurodegeneration Research, Institute of Psychiatry, King's College London, De Crespigny Park, London SE5 8AF, United Kingdom 2 Institute of Human Genetics, George August University, Goettingen, Germany 3 Departments of Pathology and Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
* Corresponding author: Dr Jean-Marc Gallo, MRC Centre for Neurodegeneration Research, King's College London, Institute of Psychiatry, Box P037, De Crespigny Park, London, SE5 8AF, United Kingdom. Tel. No. +44 20 7848 0404; Fax No. +44 20 7708 0017, E-mail: jean-marc.gallo{at}iop.kcl.ac.uk
Received July 5, 2007; Revised August 19, 2007; Accepted August 19, 2007
Elucidating the mechanisms of alternative splicing in the brain is a prerequisite to the understanding of the pathogenesis of major neurological diseases linked to impairment of pre-mRNA alternative splicing. The gene Trinucleotide Repeat Containing 4 (TNRC4) is predicted to encode a member of the CELF (CUG-BP- and ETR-3-like factors) family of RNA-binding proteins containing a 15-18 residues polyglutamine sequence. The TNRC4 transcript is selectively expressed in the brain. Using an anti-peptide antibody against the predicted sequence, we establish the presence of TNRC4 as a 
50 kDa protein in the brain. Full-length TNRC4 displays nuclear and cytoplasmic localizations in transfected cells whereas a C-terminally truncated mutant is essentially confined to the cytoplasm. TNRC4 is not recruited into inclusions formed by polyglutamine expanded ataxin-1 or huntingtin. TNRC4 activates tau exon 10 (E10) inclusion at high efficiency in transfected cells. TNRC4 contains two consecutive N-terminal RNA recognition motifs (RRM) separated from the C-terminal RRM. Deletion and point mutant analysis shows that the activity of TNRC4 on tau E10 splicing is mainly mediated by the RNA-binding activity of the second RRM and involves an intronic element of the tau pre-mRNA. The polyglutamine sequence has no effect on the activity of TNRC4 on tau E10 splicing. This study represents the first characterization of TNRC4 and provides further insight into the mechanisms of brain-specific alternative splicing and their possible pathological implications.
+ The authors wish it to be known that, in their opinion, the two first authors should be regarded as joint First Authors.
¶ Present address: Centre for Endocrinology, William Harvey Research Institute, Barts and the London, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom.
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