Complex regulation of tau exon 10, whose missplicing causes frontotemporal dementia

被引:77
作者
Gao, QS
Memmott, J
Lafyatis, R
Stamm, S
Screaton, G
Andreadis, A
机构
[1] EK Shriver Ctr Mental Retardat, Dept Biomed Sci, Waltham, MA 02454 USA
[2] Harvard Univ, Sch Med, Dept Neurol, Boston, MA USA
[3] Massachusetts Gen Hosp, Boston, MA 02114 USA
[4] Boston Univ, Sch Med, Arthrit Ctr, Boston, MA USA
[5] Max Planck Inst Neurobiol, Martinsried, Germany
[6] John Radcliffe Hosp, Inst Mol Med, Human Immunol Grp, Oxford, England
关键词
microtubule-associated protein tau; expression pattern of regulated isoforms; microtubule binding domain; regulation of alternative splicing; frontotemporal dementia;
D O I
10.1046/j.1471-4159.2000.740490.x
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
Tau is a microtubule-associated protein whose transcript undergoes complex regulated splicing in the mammalian nervous system. Exon 10 of the gene is an alternatively spliced cassette that is adult-specific and that codes for a microtubule binding domain. Recently, mutations that affect splicing of exon 10 have been shown to cause inherited frontotemporal dementia (FTDP), In this study, we establish the endogenous expression patterns of exon 10 in human tissue; by reconstituting naturally occurring FTDP mutants in the homologous context of exon 10, we show that the cis determinants of exon 10 splicing regulation include an exonic silencer within the exon, its 5' splice site, and the relative affinities of its flanking exons to it. By cotransfections in vivo, we demonstrate that several splicing regulators affect the ratio of tau isoforms by inhibiting exon 10 inclusion.
引用
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页码:490 / 500
页数:11
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