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

Chapple, J. Paul; Anthony, Karen; Martin, T. Rodriguez; Dev, Arvind; Cooper, Thomas A.; Gallo, Jean‐Marc

doi:10.1093/hmg/ddm233

Cited by 18 publications

(26 citation statements)

References 53 publications

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“…In adults, the expression of Celf3 and Gomafu is mostly restricted to the nervous system at the tissue level (Ladd et al . 2001; Chapple et al . 2007; Dev et al .…”

Section: Discussionmentioning

confidence: 99%

Formation of nuclear bodies by the lncRNA Gomafu‐associating proteins Celf3 and SF1

et al. 2014

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Gomafu/MIAT/Rncr2 is a long noncoding RNA that has been proposed to control retinal cell specification, stem cell differentiation and alternative splicing of schizophrenia-related genes. However, how Gomafu controls these biological processes at the molecular level has remained largely unknown. In this study, we identified the RNA-binding protein Celf3 as a novel Gomafu-associating protein. Knockdown of Celf3 led to the down-regulation of Gomafu, and cross-link RNA precipitation analysis confirmed specific binding between Celf3 and Gomafu. In the neuroblastoma cell line Neuro2A, Celf3 formed novel nuclear bodies (named CS bodies) that colocalized with SF1, another Gomafu-binding protein. Gomafu, however, was not enriched in the CS bodies; instead, it formed distinct nuclear bodies in separate regions in the nucleus. These observations suggest that Gomafu indirectly modulates the function of the splicing factors SF1 and Celf3 by sequestering these proteins into separate nuclear bodies.

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“…In adults, the expression of Celf3 and Gomafu is mostly restricted to the nervous system at the tissue level (Ladd et al . 2001; Chapple et al . 2007; Dev et al .…”

Section: Discussionmentioning

confidence: 99%

Formation of nuclear bodies by the lncRNA Gomafu‐associating proteins Celf3 and SF1

et al. 2014

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“…Thus, there is significant therapeutic interest in modulating the splicing of this exon. Multiple factors are known to affect MAPT exon 10 splicing (4)(5)(6)(7)(8)(9). This combinatorial control is typical of alternative splicing patterns and points to the difficulties in developing splicingtargeted therapeutics.…”

mentioning

confidence: 99%

A high-throughput screening strategy identifies cardiotonic steroids as alternative splicing modulators

Stoilov

Lin

Damoiseaux

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

125

131

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Alternative splicing has emerged as a promising therapeutic target in a number of human disorders. However, the discovery of compounds that target the splicing reaction has been hindered by the lack of suitable high-throughput screening assays. Conversely, the effects of known drugs on the splicing reaction are mostly unclear and not routinely assessed. We have developed a twocolor fluorescent reporter for cellular assays of exon inclusion that can accommodate nearly any cassette exon and minimizes interfering effects from changes in transcription and translation. We used microtubule-associated protein tau (MAPT) exon 10, whose missplicing causes frontotemporal dementia, to test the reporter in screening libraries of known bioactive compounds. These screens yielded several compounds that alter the splicing of the exon, both in the reporter and in the endogenous MAPT mRNA. One compound, digoxin, has long been used in the treatment of heart failure, but was not known to modulate splicing. The positive compounds target different signal transduction pathways, and microarray analysis shows that each compound affects the splicing of a different set of exons in addition to MAPT exon 10. Our results identify currently prescribed cardiotonic steroids as modulators of alternative splicing and demonstrate the feasibility of screening for drugs that alter exon inclusion.digoxin ͉ fluorescent reporter ͉ plant steroids ͉ MAPT ͉ FTDP-17 D isruption of exon recognition and misregulation of alternative splicing are a common cause of human disease. Conditions linked to errors in pre-mRNA splicing include autoimmune disorders, neurodegenerative diseases, cystic fibrosis, growth hormone deficiency, muscular dystrophy, and cancer progression (1-3). Thus, the RNA splicing machinery is an important potential target for drug development. However, few drugs have been identified that specifically target the splicing reaction, and the impact of existing drugs on splicing regulation is not routinely examined.One disease stemming from misregulation of alternative splicing is frontotemporal dementia with parkinsonism on chromosome 17 (FTDP-17) (4). FTDP-17 is caused by mutations affecting exon 10 of the microtubule-associated protein tau (MAPT) gene that increase inclusion of exon 10 in the mRNA. Exon 10 encodes the fourth microtubule-binding domain of the protein, and elevated levels of the four-domain form of tau evidently lead to neurofibrillary tangles and subsequent neurodegeneration. Thus, there is significant therapeutic interest in modulating the splicing of this exon. Multiple factors are known to affect MAPT exon 10 splicing (4-9). This combinatorial control is typical of alternative splicing patterns and points to the difficulties in developing splicingtargeted therapeutics. Interfering with individual factors often only partially affects a given splicing pattern, and each factor can affect many unrelated exons in addition to the therapeutic target.Finding compounds that modulate alternative splicing requires effective high-throug...

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“…A non conserved domain, the divergent domain, separates rrM3 from rrM2. Notable differences between the divergent domains of the CeLF proteins are a serine-rich region in CeLF1 (identified by primary sequence comparison), a polyglutamine stretch in CeLF3, 12,26 and specific regions in the divergent domain of CeLF4 which modulate its splicing activity on different pre-mrNA targets. 71 models of DM1 have been generated, and some tau abnormalities in the brain have been reported.…”

Section: The Celf Family Of Rna-binding Proteinsmentioning

confidence: 99%

“…12,13,25 The CELF3 transcript is translated into a bona fide ∼50 kDa protein in the brain. 26 In the mouse, CELF4 is brain-specific and is expressed in neurons at a particularly high level in the pyramidal neurons of the CA2 and CA3 regions. 27 Although little information is available to date, neuronal CELF proteins appear to be important in maintaining neuronal function.…”

Section: The Celf Family Of Rna-binding Proteinsmentioning

confidence: 99%

“…36 Also, inclusion of E10 is promoted at high efficiency in vitro by CELF3 and CELF4. 26,37 Thus, an abnormal activity of CELF proteins, including CELF2, 3 and 4, on tau splicing may be a factor contributing to neuronal pathology of DM1. Repression of tau E2/3 inclusion can be obtained by RNAi downregulation of MBNL1 in HeLa cells, suggesting that altered MBNL1 activity may also contribute to changes in tau splicing occurring in DM1.…”

Section: Implication Of Celf Proteins In Triplet Repeat Expansion Neumentioning

confidence: 99%

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The role of CELF proteins in neurological disorders

Gallo

Spickett

2010

RNA Biology

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

Cited by 18 publications

References 53 publications

Formation of nuclear bodies by the lncRNA Gomafu‐associating proteins Celf3 and SF1

Formation of nuclear bodies by the lncRNA Gomafu‐associating proteins Celf3 and SF1

A high-throughput screening strategy identifies cardiotonic steroids as alternative splicing modulators

The role of CELF proteins in neurological disorders

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