Expression, localization and tau exon 10 splicing activity of the brain RNA-binding protein TNRC4

被引:14
作者
Chapple, J. Paul
Anthony, Karen
Martin, Teresa Rodriguez
Dev, Arvind
Cooper, Thomas A.
Gallo, Jean-Marc
机构
[1] Kings Coll London, Inst Psychiat, MRC, Ctr Neurodegenerat Res, London SE5 8AF, England
[2] Univ Gottingen, Inst Human Genet, D-3400 Gottingen, Germany
[3] Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA
[4] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA
基金
英国生物技术与生命科学研究理事会;
关键词
D O I
10.1093/hmg/ddm233
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
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-residue 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 similar to 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 (RRMs) separated from the C-terminal RRM. Deletion and point mutant analysis show 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.
引用
收藏
页码:2760 / 2769
页数:10
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