Abstract
Alternative splicing plays a prevalent role in generating functionally diversified proteomes from genomes with a more limited repertoire of protein-coding genes. Alternative splicing is frequently regulated with cell type or developmental specificity and in response to signaling pathways, and its mis-regulation can lead to disease. Co-regulated programs of alternative splicing involve interplay between a host of cis-acting transcript features and trans-acting RNA-binding proteins. Here, we review the current state of understanding of the logic and mechanism of regulated alternative splicing and indicate how this understanding can be exploited to manipulate splicing for therapeutic purposes.
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References
Cooper TA, Wan L, Dreyfuss G (2009) RNA and disease. Cell 136:777–793
Muntoni F, Wood MJ (2011) Targeting RNA to treat neuromuscular disease. Nat Rev Drug Discov 10:621–637
Singh RK, Cooper TA (2012) Pre-mRNA splicing in disease and therapeutics. Trends Mol Med 18:472–482
Wang Z, Burge CB (2008) Splicing regulation: from a parts list of regulatory elements to an integrated splicing code. RNA 14:802–813
Blencowe BJ (2006) Alternative splicing: new insights from global analyses. Cell 126:37–47
Hallegger M, Llorian M, Smith CW (2010) Alternative splicing: global insights. FEBS J 277:856–866
Barash Y, Calarco JA, Gao W et al (2010) Deciphering the splicing code. Nature 465: 53–59
Zhang C, Frias MA, Mele A et al (2010) Integrative modeling defines the Nova splicing-regulatory network and its combinatorial controls. Science 329:439–443
Luco RF, Allo M, Schor IE et al (2012) Epigenetics in alternative pre-mRNA splicing. Cell 144:16–26
Burge C, Tuschl T, Sharp P (1999) Splicing of precursors to mRNAs by spliceosomes. In: Gestetland R, Cech T, Atkins J (eds) The RNA world. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp 525–560
Roca X, Krainer AR, Eperon IC (2013) Pick one, but be quick: 5′ splice sites and the problems of too many choices. Genes Dev 27:129–144
Keren H, Lev-Maor G, Ast G (2010) Alternative splicing and evolution: diversification, exon definition and function. Nat Rev Genet 11:345–355
Chasin LA (2007) Searching for splicing motifs. Adv Exp Med Biol 623:85–106
Zhang XH, Chasin LA (2004) Computational definition of sequence motifs governing constitutive exon splicing. Genes Dev 18:1241–1250
Ke S, Shang S, Kalachikov SM et al (2011) Quantitative evaluation of all hexamers as exonic splicing elements. Genome Res 21:1360–1374
Clery A, Blatter M, Allain FH (2008) RNA recognition motifs: boring? Not quite. Curr Opin Struct Biol 18:290–298
Goren A, Ram O, Amit M et al (2006) Comparative analysis identifies exonic splicing regulatory sequences: the complex definition of enhancers and silencers. Mol Cell 22:769–781
Wang Y, Ma M, Xiao X et al (2012) Intronic splicing enhancers, cognate splicing factors and context-dependent regulation rules. Nat Struct Mol Biol 19:1044–1052
Erkelenz S, Mueller WF, Evans MS et al (2013) Position-dependent splicing activation and repression by SR and hnRNP proteins rely on common mechanisms. RNA 19:96–102
Witten JT, Ule J (2011) Understanding splicing regulation through RNA splicing maps. Trends Genet 27:89–97
Siebel CW, Fresco LD, Rio DC (1992) The mechanism of somatic inhibition of Drosophila P-element pre-mRNA splicing: multiprotein complexes at an exon pseudo-5′ splice site control U1 snRNP binding. Genes Dev 6:1386–1401
Cote J, Dupuis S, Jiang Z et al (2001) Caspase-2 pre-mRNA alternative splicing: identification of an intronic element containing a decoy 3′ acceptor site. Proc Natl Acad Sci USA 98:938–943
Pagani F, Buratti E, Stuani C et al (2002) A new type of mutation causes a splicing defect in ATM. Nat Genet 30:426–429
Buratti E, Baralle FE (2004) Influence of RNA secondary structure on the pre-mRNA splicing process. Mol Cell Biol 24:10505–10514
Shepard PJ, Hertel KJ (2008) Conserved RNA secondary structures promote alternative splicing. RNA 14:1463–1469
Hiller M, Zhang Z, Backofen R et al (2007) Pre-mRNA secondary structures influence exon recognition. PLoS Genet 3:e204
Singh NN, Singh RN, Androphy EJ (2007) Modulating role of RNA structure in alternative splicing of a critical exon in the spinal muscular atrophy genes. Nucleic Acids Res 35:371–389
Grover A, Houlden H, Baker M et al (1999) 5′ splice site mutations in tau associated with the inherited dementia FTDP-17 affect a stem-loop structure that regulates alternative splicing of exon 10. J Biol Chem 274:15134–15143
Baraniak AP, Lasda EL, Wagner EJ et al (2003) A stem structure in fibroblast growth factor receptor 2 transcripts mediates cell-type-specific splicing by approximating intronic control elements. Mol Cell Biol 23: 9327–9337
Graveley BR (2005) Mutually exclusive splicing of the insect Dscam pre-mRNA directed by competing intronic RNA secondary structures. Cell 123:65–73
Olson S, Blanchette M, Park J et al (2007) A regulator of Dscam mutually exclusive splicing fidelity. Nat Struct Mol Biol 14:1134–1140
Wang X, Li G, Yang Y et al (2012) An RNA architectural locus control region involved in Dscam mutually exclusive splicing. Nat Commun 3:1255
Yang Y, Zhan L, Zhang W et al (2011) RNA secondary structure in mutually exclusive splicing. Nat Struct Mol Biol 18:159–168
Cheah MT, Wachter A, Sudarsan N et al (2007) Control of alternative RNA splicing and gene expression by eukaryotic riboswitches. Nature 447:497–500
Eperon LP, Graham IR, Griffiths AD et al (1988) Effects of RNA secondary structure on alternative splicing of pre-mRNA: is folding limited to a region behind the transcribing RNA polymerase? Cell 54:393–401
Smith CW, Nadal-Ginard B (1989) Mutually exclusive splicing of alpha-tropomyosin exons enforced by an unusual lariat branch point location: implications for constitutive splicing. Cell 56:749–758
Berget SM (1995) Exon recognition in vertebrate splicing. J Biol Chem 270:2411–2414
Sorek R, Shamir R, Ast G (2004) How prevalent is functional alternative splicing in the human genome? Trends Genet 20:68–71
Burnette JM, Miyamoto-Sato E, Schaub MA et al (2005) Subdivision of large introns in Drosophila by recursive splicing at nonexonic elements. Genetics 170:661–674
Schwartz S, Meshorer E, Ast G (2009) Chromatin organization marks exon-intron structure. Nat Struct Mol Biol 16:990–995
Tilgner H, Nikolaou C, Althammer S et al (2009) Nucleosome positioning as a determinant of exon recognition. Nat Struct Mol Biol 16:996–1001
Lavigueur A, La Branche H, Kornblihtt AR et al (1993) A splicing enhancer in the human fibronectin alternate ED1 exon interacts with SR proteins and stimulates U2 snRNP binding. Genes Dev 7:2405–2417
Graveley BR, Hertel KJ, Maniatis T (1998) A systematic analysis of the factors that determine the strength of pre-mRNA splicing enhancers. EMBO J 17:6747–6756
Scadden ADJ, Smith CWJ (1995) Interactions between the terminal bases of mammalian introns are retained in inosine-containing pre-mRNAs. EMBO J 14:3236–3246
Rueter SM, Dawson TR, Emeson RB (1999) Regulation of alternative splicing by RNA editing. Nature 399:75–80
Lev-Maor G, Sorek R, Levanon EY et al (2007) RNA-editing-mediated exon evolution. Genome Biol 8:R29
Dominissini D, Moshitch-Moshkovitz S, Schwartz S et al (2012) Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature 485:201–206
Shukla S, Kavak E, Gregory M et al (2011) CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing. Nature 479:74–79
Kishore S, Khanna A, Zhang Z et al (2010) The snoRNA MBII-52 (SNORD 115) is processed into smaller RNAs and regulates alternative splicing. Hum Mol Genet 19: 1153–1164
Kishore S, Stamm S (2006) The snoRNA HBII-52 regulates alternative splicing of the serotonin receptor 2C. Science 311:230–232
Park JW, Parisky K, Celotto AM et al (2004) Identification of alternative splicing regulators by RNA interference in Drosophila. Proc Natl Acad Sci USA 101:15974–15979
Saltzman AL, Pan Q, Blencowe BJ (2011) Regulation of alternative splicing by the core spliceosomal machinery. Genes Dev 25: 373–384
O’Reilly D, Dienstbier M, Cowley SA et al (2012) Differentially expressed, variant U1 snRNAs regulate gene expression in human cells. Genome Res 23:281–291
Krainer AR, Mayeda A, Kozak D et al (1991) Functional expression of cloned human splicing factor SF2: homology to RNA-binding proteins, U1 70K, and Drosophila splicing regulators. Cell 66:383–394
Ge H, Manley JL (1990) A protein factor, ASF, controls cell-specific alternative splicing of SV40 early pre-mRNA in vitro. Cell 62:25–34
Kanopka A, Muhlemann O, Akusjarvi G (1996) Inhibition by SR proteins of splicing of a regulated adenovirus pre-mRNA. Nature 381:535–538
Long JC, Caceres JF (2009) The SR protein family of splicing factors: master regulators of gene expression. Biochem J 417:15–27
Shepard PJ, Hertel KJ (2009) The SR protein family. Genome Biol 10:242
Zahler AM, Lane WS, Stolk JA et al (1992) SR proteins: a conserved family of pre-mRNA splicing factors. Genes Dev 6:837–847
Wahl MC, Will CL, Luhrmann R (2009) The spliceosome: design principles of a dynamic RNP machine. Cell 136:701–718
Sapra AK, Ankö M-L, Grishina I et al (2009) SR protein family members display diverse activities in the formation of nascent and mature mRNPs in vivo. Mol cell 34: 179–190
Tacke R, Manley JL (1995) The human splicing factors ASF/SF2 and SC35 possess distinct, functionally significant RNA binding specificities. EMBO J 14:3540–3551
Liu HX, Zhang M, Krainer AR (1998) Identification of functional exonic splicing enhancer motifs recognized by individual SR proteins. Genes Dev 12:1998–2012
Änkö M-L, Müller-McNicoll M, Brandl H et al (2012) The RNA-binding landscapes of two SR proteins reveal unique functions and binding to diverse RNA classes. Genome Biol 13:R17
Graveley BR, Hertel KJ, Maniatis T (2001) The role of U2AF35 and U2AF65 in enhancer-dependent splicing. RNA 7:806–818
Shin C, Feng Y, Manley JL (2004) Dephosphorylated SRp38 acts as a splicing repressor in response to heat shock. Nature 427:553–558
Shin C, Manley JL (2002) The SR protein SRp38 represses splicing in M phase cells. Cell 111:407–417
Feng Y, Chen M, Manley JL (2008) Phosphorylation switches the general splicing repressor SRp38 to a sequence-specific activator. Nat Struct Mol Biol 15:1040–1048
Huelga SC, Vu AQ, Arnold JD et al (2012) Integrative genome-wide analysis reveals cooperative regulation of alternative splicing by hnRNP proteins. Cell Rep 1:167–178
Boutz PL, Stoilov P, Li Q et al (2007) A post-transcriptional regulatory switch in polypyrimidine tract-binding proteins reprograms alternative splicing in developing neurons. Genes Dev 21:1636–1652
Rossbach O, Hung LH, Schreiner S et al (2009) Auto- and cross-regulation of the hnRNP L proteins by alternative splicing. Mol Cell Biol 29:1442–1451
Castle JC, Zhang C, Shah JK et al (2008) Expression of 24,426 human alternative splicing events and predicted cis regulation in 48 tissues and cell lines. Nat Genet 40: 1416–1425
Wang ET, Sandberg R, Luo S et al (2008) Alternative isoform regulation in human tissue transcriptomes. Nature 456:470–476
Wang ET, Cody NA, Jog S et al (2012) Transcriptome-wide regulation of pre-mRNA splicing and mRNA localization by muscleblind proteins. Cell 150:710–724
Tuerk C, Gold L (1990) Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. Science 249:505–510
Ray D, Kazan H, Chan ET et al (2009) Rapid and systematic analysis of the RNA recognition specificities of RNA-binding proteins. Nat Biotechnol 27:667–670
Barbosa-Morais NL, Irimia M, Pan Q et al (2012) The evolutionary landscape of alternative splicing in vertebrate species. Science 338:1587–1593
Merkin J, Russell C, Chen P, Burge CB (2012) Evolutionary dynamics of gene and isoform regulation in Mammalian tissues. Science 338:1593–1599
Lopez AJ (1998) Alternative splicing of pre-mRNA: developmental consequences and mechanisms of regulation. Annu Rev Genet 32:279–305
Llorian M, Schwartz S, Clark TA et al (2010) Position-dependent alternative splicing activity revealed by global profiling of alternative splicing events regulated by PTB. Nat Struct Mol Biol 17:1114–1123
Buckanovich RJ, Posner JB, Darnell RB (1993) Nova, the paraneoplastic Ri antigen, is homologous to an RNA-binding protein and is specifically expressed in the developing motor system. Neuron 11:657–672
Calarco JA, Superina S, O’Hanlon D et al (2009) Regulation of vertebrate nervous system alternative splicing and development by an SR-related protein. Cell 138:898–910
Warzecha CC, Sato TK, Nabet B et al (2009) ESRP1 and ESRP2 are epithelial cell-type-specific regulators of FGFR2 splicing. Mol Cell 33:591–601
Makeyev EV, Zhang J, Carrasco MA et al (2007) The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing. Mol Cell 27:435–448
Spellman R, Llorian M, Smith CW (2007) Crossregulation and functional redundancy between the splicing regulator PTB and its paralogs nPTB and ROD1. Mol Cell 27:420–434
Zheng S, Gray EE, Chawla G et al (2012) PSD-95 is post-transcriptionally repressed during early neural development by PTBP1 and PTBP2. Nat Neurosci 15:381–388, S1
Licatalosi DD, Yano M, Fak JJ et al (2012) Ptbp2 represses adult-specific splicing to regulate the generation of neuronal precursors in the embryonic brain. Genes Dev 26:1626–1642
Ye J, Llorian M, Cardona M et al (2013) A pathway involving HDAC5, cFLIP and caspases regulates expression of the splicing regulator Polypyrimidine Tract Binding Protein in the heart. J Cell Sci 126:1682–1691
Anczukow O, Rosenberg AZ, Akerman M et al (2012) The splicing factor SRSF1 regulates apoptosis and proliferation to promote mammary epithelial cell transformation. Nat Struct Mol Biol 19:220–228
Karni R, de Stanchina E, Lowe SW et al (2007) The gene encoding the splicing factor SF2/ASF is a proto-oncogene. Nat Struct Mol Biol 14:185–193
Kalsotra A, Xiao X, Ward AJ et al (2008) A postnatal switch of CELF and MBNL proteins reprograms alternative splicing in the developing heart. Proc Natl Acad Sci USA 105:20333–20338
Kalsotra A, Wang K, Li PF et al (2010) MicroRNAs coordinate an alternative splicing network during mouse postnatal heart development. Genes Dev 24:653–658
Goers ES, Purcell J, Voelker RB et al (2010) MBNL1 binds GC motifs embedded in pyrimidines to regulate alternative splicing. Nucleic Acids Res 38:2467–2484
Miller JW, Urbinati CR, Teng-Umnuay P et al (2000) Recruitment of human muscleblind proteins to (CUG)(n) expansions associated with myotonic dystrophy. EMBO J 19: 4439–4448
Kuyumcu-Martinez NM, Wang GS, Cooper TA (2007) Increased steady-state levels of CUGBP1 in myotonic dystrophy 1 are due to PKC-mediated hyperphosphorylation. Mol Cell 28:68–78
Tripathi V, Ellis JD, Shen Z et al (2010) The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. Mol Cell 39:925–938
Shin C, Manley JL (2004) Cell signalling and the control of pre-mRNA splicing. Nat Rev Mol Cell Biol 5:727–738
Lynch KW (2007) Regulation of alternative splicing by signal transduction pathways. Adv Exp Med Biol 623:161–174
Heyd F, Lynch KW (2011) Degrade, move, regroup: signaling control of splicing proteins. Trends Biochem Sci 36:397–404
Ellisen LW, Palmer RE, Maki RG et al (2001) Cascades of transcriptional induction during human lymphocyte activation. Eur J Cell Biol 80:321–328
Teague TK, Hildeman D, Kedl RM et al (1999) Activation changes the spectrum but not the diversity of genes expressed by T cells. Proc Natl Acad Sci USA 96:12691–12696
Oberdoerffer S, Moita LF, Neems D et al (2008) Regulation of CD45 alternative splicing by heterogeneous ribonucleoprotein, hnRNPLL. Science 321:686–691
Heyd F, Lynch KW (2010) Phosphorylation-dependent regulation of PSF by GSK3 controls CD45 alternative splicing. Mol Cell 40:126–137
Cho S, Hoang A, Sinha R et al (2011) Interaction between the RNA binding domains of Ser-Arg splicing factor 1 and U1-70K snRNP protein determines early spliceosome assembly. Proc Natl Acad Sci USA 108:8233–8238
Amin EM, Oltean S, Hua J et al (2011) WT1 mutants reveal SRPK1 to be a downstream angiogenesis target by altering VEGF splicing. Cancer Cell 20:768–780
Zhou Z, Qiu J, Liu W et al (2012) The Akt-SRPK-SR axis constitutes a major pathway in transducing EGF signaling to regulate alternative splicing in the nucleus. Mol Cell 47: 422–433
Fumagalli S, Totty NF, Hsuan JJ et al (1994) A target for Src in mitosis. Nature 368: 871–874
Taylor SJ, Shalloway D (1994) An RNA-binding protein associated with Src through its SH2 and SH3 domains in mitosis. Nature 368:867–871
Vernet C, Artzt K (1997) STAR, a gene family involved in signal transduction and activation of RNA. Trends Genet 13:479–484
Matter N, Herrlich P, König H (2002) Signal-dependent regulation of splicing via phosphorylation of Sam68. Nature 420:691–695
Batsché E, Yaniv M, Muchardt C (2006) The human SWI/SNF subunit Brm is a regulator of alternative splicing. Nat Struct Mol Biol 13:22–29
Cheng C, Sharp PA (2006) Regulation of CD44 alternative splicing by SRm160 and its potential role in tumor cell invasion. Mol Cell Biol 26:362–370
Moore MJ, Wang Q, Kennedy CJ et al (2010) An alternative splicing network links cell-cycle control to apoptosis. Cell 142:625–636
Paronetto MP, Achsel T, Massiello A et al (2007) The RNA-binding protein Sam68 modulates the alternative splicing of Bcl-x. J Cell Biol 176:929–939
Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70
Dhillon AS, Hagan S, Rath O et al (2007) MAP kinase signalling pathways in cancer. Oncogene 26:3279–3290
Irby RB, Yeatman TJ (2000) Role of Src expression and activation in human cancer. Oncogene 19:5636–5642
Paronetto MP, Venables JP, Elliott DJ et al (2003) Tr-kit promotes the formation of a multimolecular complex composed by Fyn, PLCgamma1 and Sam68. Oncogene 22:8707–8715
Zhu J, Mayeda A, Krainer AR (2001) Exon identity established through differential antagonism between exonic splicing silencer-bound hnRNP A1 and enhancer-bound SR proteins. Mol Cell 8:1351–1361
Jamison SF, Crow A, Garcia-Blanco MA (1992) The spliceosome assembly pathway in mammalian extracts. Mol Cell Biol 12: 4279–4287
Michaud S, Reed R (1991) An ATP-independent complex commits pre-mRNA to the mammalian spliceosome assembly pathway. Genes Dev 5:2534–2546
Michaud S, Reed R (1993) A functional association between the 5′ and 3′ splice site is established in the earliest prespliceosome complex (E) in mammals. Genes Dev 7:1008–1020
Sharma S, Falick AM, Black DL (2005) Polypyrimidine tract binding protein blocks the 5′ splice site-dependent assembly of U2AF and the prespliceosomal E complex. Mol Cell 19:485–496
Wu JY, Maniatis T (1993) Specific interactions between proteins implicated in splice site selection and regulated alternative splicing. Cell 75:1061–1070
Forch P, Puig O, Martinez C et al (2002) The splicing regulator TIA-1 interacts with U1-C to promote U1 snRNP recruitment to 5′ splice sites. EMBO J 21:6882–6892
Singh R, Valcarcel J, Green MR (1995) Distinct binding specificities and functions of higher eukaryotic polypyrimidine tract-binding proteins. Science 268:1173–1176
Lim SR, Hertel KJ (2004) Commitment to splice site pairing coincides with A complex formation. Mol Cell 15:477–483
Kotlajich MV, Crabb TL, Hertel KJ (2009) Spliceosome assembly pathways for different types of alternative splicing converge during commitment to splice site pairing in the A complex. Mol Cell Biol 29:1072–1082
Hodson MJ, Hudson AJ, Cherny D et al (2012) The transition in spliceosome assembly from complex E to complex A purges surplus U1 snRNPs from alternative splice sites. Nucleic Acids Res 40:6850–6862
Yu Y, Maroney PA, Denker JA et al (2008) Dynamic regulation of alternative splicing by silencers that modulate 5′ splice site competition. Cell 135:1224–1236
Shen H, Green MR (2004) A pathway of sequential arginine-serine-rich domain-splicing signal interactions during mammalian spliceosome assembly. Mol Cell 16:363–373
Shen H, Green MR (2006) RS domains contact splicing signals and promote splicing by a common mechanism in yeast through humans. Genes Dev 20:1755–1765
Hoskins AA, Friedman LJ, Gallagher SS et al (2011) Ordered and dynamic assembly of single spliceosomes. Science 331:1289–1295
Tseng CK, Cheng SC (2008) Both catalytic steps of nuclear pre-mRNA splicing are reversible. Science 320:1782–1784
Lallena MJ, Chalmers KJ, Llamazares S et al (2002) Splicing regulation at the second catalytic step by Sex-lethal involves 3′ splice site recognition by SPF45. Cell 109:285–296
Schneider M, Will CL, Anokhina M et al (2010) Exon definition complexes contain the tri-snRNP and can be directly converted into B-like precatalytic splicing complexes. Mol Cell 38:223–235
Bonnal S, Martinez C, Forch P et al (2008) RBM5/Luca-15/H37 regulates Fas alternative splice site pairing after exon definition. Mol Cell 32:81–95
House AE, Lynch KW (2006) An exonic splicing silencer represses spliceosome assembly after ATP-dependent exon recognition. Nat Struct Mol Biol 13:937–944
Sharma S, Kohlstaedt LA, Damianov A et al (2008) Polypyrimidine tract binding protein controls the transition from exon definition to an intron defined spliceosome. Nat Struct Mol Biol 15:183–191
Sharma S, Maris C, Allain FH et al (2011) U1 snRNA directly interacts with polypyrimidine tract-binding protein during splicing repression. Mol Cell 41:579–588
Izquierdo JM, Majos N, Bonnal S et al (2005) Regulation of Fas alternative splicing by antagonistic effects of TIA-1 and PTB on exon definition. Mol Cell 19:475–484
Chiou N-T, Shankarling G, Lynch KW (2013) HnRNP L and HnRNP A1 induce extended U1 snRNA interactions with an exon to repress spliceosome assembly. Mol Cell 49:972–982
Motta-Mena LB, Heyd F, Lynch KW (2010) Context-dependent regulatory mechanism of the splicing factor hnRNP L. Mol Cell 37: 223–234
Lim KH, Ferraris L, Filloux ME et al (2011) Using positional distribution to identify splicing elements and predict pre-mRNA processing defects in human genes. Proc Natl Acad Sci USA 108:11093–11098
Muntoni F, Torelli S, Ferlini A (2003) Dystrophin and mutations: one gene, several proteins, multiple phenotypes. Lancet Neurol 2:731–740
Yokota T, Lu Q-L, Partridge T et al (2009) Efficacy of systemic morpholino exon-skipping in Duchenne dystrophy dogs. Ann Neurol 65:667–676
Lorson CL, Hahnen E, Androphy EJ et al (1999) A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci USA 96:6307–6311
Nlend Nlend R, Meyer K, Schümperli D (2010) Repair of pre-mRNA splicing: prospects for a therapy for spinal muscular atrophy. RNA Biol 7:430–440
Skordis LA, Dunckley MG, Yue B et al (2003) Bifunctional antisense oligonucleotides provide a trans-acting splicing enhancer that stimulates SMN2 gene expression in patient fibroblasts. Proc Natl Acad Sci USA 100:4114–4119
Cartegni L, Krainer AR (2003) Correction of disease-associated exon skipping by synthetic exon-specific activators. Nat Struct Biol 10:120–125
Singh NK, Singh NN, Androphy EJ et al (2006) Splicing of a critical exon of human Survival Motor Neuron is regulated by a unique silencer element located in the last intron. Mol Cell Biol 26:1333–1346
Hua Y, Sahashi K, Hung G et al (2010) Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model. Genes Dev 24: 1634–1644
Passini MA, Bu J, Richards AM et al (2011) Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy. Sci Transl Med 3: 72ra18
Black DL (1991) Does steric interference between splice sites block the splicing of a short c-src neuron-specific exon in non-neuronal cells? Genes Dev 5:389–402
Underwood JG, Boutz PL, Dougherty JD et al (2005) Homologues of the Caenorhabditis elegans Fox-1 protein are neuronal splicing regulators in mammals. Mol Cell Biol 25:10005–10016
Matlin AJ, Southby J, Gooding C et al (2007) Repression of alpha-actinin SM exon splicing by assisted binding of PTB to the polypyrimidine tract. RNA 13:1214–1223
Acknowledgments
Work in the authors’ lab is supported by grants from the Wellcome Trust (092900) and the Biotechnology and Biological Sciences Research Council (BB/H004203/1 and BB/J0014567/1).
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Coelho, M.B., Smith, C.W.J. (2014). Regulation of Alternative Pre-mRNA Splicing. In: Hertel, K. (eds) Spliceosomal Pre-mRNA Splicing. Methods in Molecular Biology, vol 1126. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-980-2_5
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