The splicing determinants of a regulated exon in the axonal MAP tau reside within the exon and in its upstream intron

Wei, Mei‐Ling; Memmott, John; Screaton, Gavin; Andreadis, Athena

doi:10.1016/s0169-328x(00)00137-6

Cited by 18 publications

(28 citation statements)

References 88 publications

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“…3b, lane 1) of exon 6 suggest complex regulation by splicing activators and inhibitors. Our previous work showed that several factors influence the splicing of exon 6: PTB inhibits all three exon 6 variants, U2AF increases 6p in SV6 and 6 + in C1C2 (Wei et al . 2000).…”

Section: Resultsmentioning

confidence: 99%

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Tau exon 6 is regulated by an intricate interplay of trans factors and cis elements, including multiple branch points

Wang

Tse

Andreadis

2006

Journal of Neurochemistry

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Tau is a microtubule-associated protein whose transcript undergoes complex regulated splicing in the mammalian nervous system. Exon 6 of the gene is an alternatively spliced cassette whose expression profile differs from that of the other tau regulated exons, implying the involvement of distinct regulatory factors. Previous work had established the existence and use of two additional 3¢ splice sites within exon 6 and the influence of splicing factors polypyrimidine binding protein (PTB) and U2AF on its splicing. The present work shows that exon 6 isoforms exist in distinct ratios in different compartments of the nervous system and that splicing of exon 6 is governed by multiple branch points, exonic cis elements and additional trans factors. Recent results show that tau exon 6 is specifically suppressed in the brains of people who suffer from myotonic dystrophy type 1. The understanding of how tau exon 6 splicing is regulated may give us insights into the disease. Keywords alternative splicing, cis regulatory elements, cryptic splice site, microtubule-associated protein tau, myotonic dystrophy, trans splicing regulators.

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Section: Resultsmentioning

confidence: 99%

“…1992) and is strongly involved in its regulation. Splicing factors U2AF and polypyrimidine binding protein (PTB), which exert their effects on the BP/PPT region, influence the ratios of the exon 6 species (Wei et al . 2000).…”

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confidence: 99%

Tau exon 6 is regulated by an intricate interplay of trans factors and cis elements, including multiple branch points

Wang

Tse

Andreadis

2006

Journal of Neurochemistry

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“…Several studies have been conducted to characterize this region to elucidate molecular mechanisms of these splicing mutations and their effects on tau exon 10 alternative splicing (Wei et al 2000; Hartmann et al 2001; Broderick et al 2004; Kondo et al 2004; Glatz et al 2006; Kar et al 2006; Wu et al 2006; Dawson et al 2007; Gao et al 2007; Zhou et al 2008; Wang et al 2010; Kar et al 2011). These studies have uncovered several transacting proteins that interact with exonic or intronic cis-elements to regulate tau exon 10 alternative splicing.…”

Section: Discussionmentioning

confidence: 99%

PSF Suppresses Tau Exon 10 Inclusion by Interacting with a Stem-Loop Structure Downstream of Exon 10

Ray

Kar²,

Fushimi³

et al. 2011

J Mol Neurosci

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Microtubule binding protein Tau has been implicated in a wide range of neurodegenerative disorders collectively classified as tauopathies. Exon 10 of the human tau gene, which codes for a microtubule binding repeat region, is alternatively spliced to form Tau protein isoforms containing either four or three microtubule binding repeats, Tau4R and Tau3R, respectively. The levels of different Tau splicing isoforms are fine-tuned by alternative splicing with the ratio of Tau4R/Tau3R maintained approximately at one in adult neurons. Mutations that disrupt tau exon 10 splicing regulation cause an imbalance of different tau splicing isoforms and have been associated with tauopathy. To search for factors interacting with tau pre-messenger RNA (pre-mRNA) and regulating tau exon 10 alternative splicing, we performed a yeast RNA–protein interaction screen and identified polypyrimidine tract binding protein associated splicing factor (PSF) as a candidate tau exon 10 splicing regulator. UV crosslinking experiments show that PSF binds to the stem-loop structure at the 5′ splice site downstream of tau exon 10. This PSF-interacting RNA element is distinct from known PSF binding sites previously identified in other genes. Overexpression of PSF promotes tau exon 10 exclusion, whereas down-regulation of the endogenous PSF facilitates exon 10 inclusion. Immunostaining shows that PSF is expressed in the human brain regions affected by tauopathy. Our data reveal a new player in tau exon 10 alternative splicing regulation and uncover a previously unknown mechanism of PSF in regulating tau pre-mRNA splicing.

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“…Previous study by our laboratory [Wei and Andreadis, 1998;Wei et al, 2000] showed that exon 6 is not strictly a cassette, as originally believed [Himmler, 1989]. Instead, besides its canonical 3 0 splice site, exon 6 utilizes two additional 3 0 splice sites (Fig.…”

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confidence: 84%

Tau isoforms which contain the domain encoded by exon 6 and their role in neurite elongation

Luo¹,

Leski²,

Andreadis³

2004

J of Cellular Biochemistry

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The regulation of tau protein expression during different stages of cellular differentiation and development as well as its functional role in morphogenesis, neurofibrillary tangle formation, and neurodegeneration have been topics of extensive study but have not been completely clarified yet. Tau undergoes complex regulated splicing in the mammalian nervous system. Our previous study with tau exon 6 demonstrated that it shows a splicing regulation profile which is distinct from that of the other tau exons as well as a unique expression pattern which is spatially and temporally regulated. In this study, we investigated the expression, localization, and effects of tau isoforms which contain exon 6 in neuroblastoma cells which stably overexpress them. We found that expression of one particular combination of tau exons (the longest adult isoform plus the domain of exon 6) significantly inhibits neurite elongation.

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The splicing determinants of a regulated exon in the axonal MAP tau reside within the exon and in its upstream intron

Cited by 18 publications

References 88 publications

Tau exon 6 is regulated by an intricate interplay of trans factors and cis elements, including multiple branch points

Tau exon 6 is regulated by an intricate interplay of trans factors and cis elements, including multiple branch points

PSF Suppresses Tau Exon 10 Inclusion by Interacting with a Stem-Loop Structure Downstream of Exon 10

Tau isoforms which contain the domain encoded by exon 6 and their role in neurite elongation

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