Skip to main content

Advertisement

SpringerLink
Log in

The Evolution of Alternative Splicing in the Pax Family: The View from the Basal Chordate Amphioxus

  • Published:
Journal of Molecular Evolution Aims and scope Submit manuscript

Abstract

Pax genes encode transcription factors critical for metazoan development. Large-scale gene duplication with subsequent gene losses during vertebrate evolution has resulted in two human genes for each of the Pax1/9, Pax3/7, and Pax4/6 subfamilies and three for the Pax2/5/8 subfamily, compared to one each in the cephalochordate amphioxus. In addition, alternative splicing occurs in vertebrate Pax transcripts from all four subfamilies, and many splice forms are known to have functional importance. To better understand the evolution of alternative splicing within the Pax family, we systematically surveyed transcripts of the four amphioxus Pax genes. We have found alternative splicing in every gene. Comparisons with vertebrates suggest that the number of alternative splicing events per gene has not decreased following duplication; there are comparable levels in the four amphioxus Pax genes as in each gene of the equivalent vertebrate families. Thus, the total number of isoforms for the nine vertebrate genes is considerably higher than for the four amphioxus genes. Most alternative splicing events appear to have arisen since the divergence of amphioxus and vertebrate lineages, suggesting that differences in alternative splicing could account for divergent functions of the highly conserved Pax genes in both lineages. However, several events predicted to dramatically alter known functional domains are conserved between amphioxus and vertebrates, suggestive of a common chordate function. Our results, together with previous studies of vertebrate Pax genes, support the theory that alternative splicing impacts functional motifs more than gene duplication followed by divergence.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Anspach J, Poulsen G, Kaattari I, Pollock R, Zwollo P (2001) Reduction in DNA binding activity of the transcription factor Pax-5a in B lymphocytes of aged mice. J Immunol 166:2617–2626

    PubMed  CAS  Google Scholar 

  • Azuma N, Tadokoro K, Asaka A, Yamada M, Yamaguchi Y, Handa H, Matsushima S, Watanabe T, Kohsaka S, Kida Y, Shiraishi T, Ogura T, Shimamura K, Nakafuku M (2005) The Pax6 isoform bearing an alternative spliced exon promotes the development of the neural retinal structure. Hum Mol Genet 14:735–745

    PubMed  CAS  Google Scholar 

  • Balczarek KA, Lai ZC, Kumar S (1997) Evolution of functional diversification of the paired box (Pax) DNA-binding domains. Mol Biol Evol 14:829–842

    PubMed  CAS  Google Scholar 

  • Bandah D, Swissa T, Ben-Shlomo G, Banin E, Ofri R, Sharon D (2007) A complex expression pattern of Pax6 in the pigeon retina. Invest Ophthalmol Vis Sci 48:2503–2509

    PubMed  Google Scholar 

  • Barber TD, Barber MC, Cloutier TE, Friedman TB (1999) PAX3 gene structure, alternative splicing and evolution. Gene 237:311–319

    PubMed  CAS  Google Scholar 

  • Barr FG, Fitzgerald JC, Ginsberg JP, Vanella ML, Davis RJ, Bennicelli JL (1999) Predominant expression of alternative PAX3 and PAX7 forms in myogenic and neural tumor cell lines. Cancer Res 59:5443–5448

    PubMed  CAS  Google Scholar 

  • Blair JE, Hedges SB (2005) Molecular phylogeny and divergence times of deuterostome animals. Mol Biol Evol 22:2275–22784

    PubMed  CAS  Google Scholar 

  • Blencowe BJ (2006) Alternative splicing: new insights from global analyses. Cell 126:37–47

    PubMed  CAS  Google Scholar 

  • Borson ND, Lacy MQ, Wettstein PJ (2002) Altered mRNA expression of Pax5 and Blimp-1 in B cells in multiple myeloma. Blood 100:4629–4639

    PubMed  CAS  Google Scholar 

  • Bourlat SJ, Juliusdottir T, Lowe CJ, Freeman R, Aronowicz J, Kirschner M, Lander ES, Thorndyke M, Nakano H, Kohn AB, Heyland A, Moroz LL, Copley RR, Telford MJ (2006) Deuterostome phylogeny reveals monophyletic chordates and the new phylum Xenoturbellida. Nature 444:85–88

    PubMed  CAS  Google Scholar 

  • Bruun JA, Thomassen EI, Kristiansen K, Tylden G, Holm T, Mikkola I, Bjorkoy G, Johansen T (2005) The third helix of the homeodomain of paired class homeodomain proteins acts as a recognition helix both for DNA and protein interactions. Nucleic Acids Res 33:2661–2675

    PubMed  CAS  Google Scholar 

  • Carriere C, Plaza S, Martin P, Quatannens B, Bailly M, Stehelin D, Saule S (1993) Characterization of quail Pax-6 (Pax-QNR) proteins expressed in the neuroretina. Mol Cell Biol 13:7257–7266

    PubMed  CAS  Google Scholar 

  • Chalepakis G, Jones FS, Edelman GM, Gruss P (1994) Pax-3 contains domains for transcription activation and transcription inhibition. Proc Natl Acad Sci USA 91:12745–12749

    PubMed  CAS  Google Scholar 

  • Chi N, Epstein JA (2002) Getting your Pax straight: pax proteins in development and disease. Trends Genet 18:41–47

    PubMed  CAS  Google Scholar 

  • Conti E, Izaurralde E (2005) Nonsense-mediated mRNA decay: molecular insights and mechanistic variations across species. Curr Opin Cell Biol 17:316–325

    PubMed  CAS  Google Scholar 

  • Czerny T, Busslinger M (1995) DNA-binding and transactivation properties of Pax-6: three amino acids in the paired domain are responsible for the different sequence recognition of Pax-6 and BSAP (Pax-5). Mol Cell Biol 15:2858–2871

    PubMed  CAS  Google Scholar 

  • Czerny T, Schaffner G, Busslinger M (1993) DNA sequence recognition by Pax proteins: bipartite structure of the paired domain and its binding site. Genes Dev 7:2048–2061

    PubMed  CAS  Google Scholar 

  • de la Grange P, Dutertre M, Martin N, Auboeuf D (2005) FAST DB: a website resource for the study of the expression regulation of human gene products. Nucleic Acids Res 33:4276–4284

    Google Scholar 

  • Dorfler P, Busslinger M (1996) C-terminal activating and inhibitory domains determine the transactivation potential of BSAP (Pax-5), Pax-2 and Pax-8. EMBO J 15:1971–1982

    PubMed  CAS  Google Scholar 

  • Eberhard D, Jimenez G, Heavey B, Busslinger M (2000) Transcriptional repression by Pax5 (BSAP) through interaction with corepressors of the Groucho family. EMBO J 19:2292–2303

    PubMed  CAS  Google Scholar 

  • Epstein J, Cai J, Glaser T, Jepeal L, Maas R (1994) Identification of a Pax paired domain recognition sequence and evidence for DNA-dependent conformational changes. J Biol Chem 269:8355–8361

    PubMed  CAS  Google Scholar 

  • Fujitani Y, Kajimoto Y, Yasuda T, Matsuoka TA, Kaneto H, Umayahara Y, Fujita N, Watada H, Miyazaki JI, Yamasaki Y, Hori M (1999) Identification of a portable repression domain and an E1A-responsive activation domain in Pax4: a possible role of Pax4 as a transcriptional repressor in the pancreas. Mol Cell Biol 19:8281–8291

    PubMed  CAS  Google Scholar 

  • Glardon S, Holland LZ, Gehring WJ, Holland ND (1998) Isolation and developmental expression of the amphioxus Pax-6 gene (AmphiPax-6): insights into eye and photoreceptor evolution. Development 125:2701–2710

    PubMed  CAS  Google Scholar 

  • Gorlov IP, Saunders GF (2002) A method for isolating alternatively spliced isoforms: isolation of murine Pax6 isoforms. Anal Biochem 308:401–404

    PubMed  CAS  Google Scholar 

  • Graveley BR (2001) Alternative splicing: increasing diversity in the proteomic world. Trends Genet 17:100–107

    PubMed  CAS  Google Scholar 

  • Hanson IM, Seawright A, Hardman K, Hodgson S, Zaletayev D, Fekete G, van Heyningen V (1993) PAX6 mutations in aniridia. Hum Mol Genet 2:915–920

    PubMed  CAS  Google Scholar 

  • Heller N, Brändli AW (1997) Xenopus Pax-2 displays multiple splice forms during embryogenesis and pronephric kidney development. Mech Dev 69:83–104

    PubMed  CAS  Google Scholar 

  • Heller N, Brändli AW (1999) Xenopus Pax-2/5/8 orthologues: novel insights into Pax gene evolution and identification of Pax-8 as the earliest marker for otic and pronephric cell lineages. Dev Genet 24:208–219

    PubMed  CAS  Google Scholar 

  • Hetzer-Egger C, Schorpp M, Boehm T (2000) Evolutionary conservation of gene structures of the Pax1/9 gene family. Biochim Biophys Acta 1492:517–521

    PubMed  CAS  Google Scholar 

  • Holland PW (2003) More genes in vertebrates? J Struct Funct Genomics 3:75–84

    PubMed  CAS  Google Scholar 

  • Holland LZ, Yu JK (2004) Cephalochordate (amphioxus) embryos: procurement, culture, and basic methods. Methods Cell Biol 74:195–215

    Article  PubMed  Google Scholar 

  • Holland ND, Holland LZ, Kozmik Z (1995) An amphioxus Pax gene, AmphiPax-1, expressed in embryonic endoderm, but not in mesoderm: implications for the evolution of class I paired box genes. Mol Mar Biol Biotechnol 4:206–214

    PubMed  CAS  Google Scholar 

  • Holland LZ, Schubert M, Kozmik Z, Holland ND (1999) AmphiPax3/7, an amphioxus paired box gene: insights into chordate myogenesis, neurogenesis, and the possible evolutionary precursor of definitive vertebrate neural crest. Evol Dev 1:153–165

    PubMed  CAS  Google Scholar 

  • Holland LZ, Laudet V, Schubert M (2004) The chordate amphioxus: an emerging model organism for developmental biology. Cell Mol Life Sci 61:2290–2308

    PubMed  CAS  Google Scholar 

  • Hoshiyama D, Iwabe N, Miyata T (2007) Evolution of the gene families forming the Pax/Six regulatory network: isolation of genes from primitive animals and molecular phylogenetic analyses. FEBS Lett 581:1639–1643

    PubMed  CAS  Google Scholar 

  • Inoue H, Nomiyama J, Nakai K, Matsutani A, Tanizawa Y, Oka Y (1998) Isolation of full-length cDNA of mouse PAX4 gene and identification of its human homologue. Biochem Biophys Res Commun 243:628–633

    PubMed  CAS  Google Scholar 

  • Jaworski C, Sperbeck S, Graham C, Wistow G (1997) Alternative splicing of Pax6 in bovine eye and evolutionary conservation of intron sequences. Biochem Biophys Res Commun 240:196–202

    PubMed  CAS  Google Scholar 

  • Jun S, Desplan C (1996) Cooperative interactions between paired domain and homeodomain. Development 122:2639–2650

    PubMed  CAS  Google Scholar 

  • Jun S, Wallen RV, Goriely A, Kalionis B, Desplan C (1998) Lune/eye gone, a Pax-like protein, uses a partial paired domain and a homeodomain for DNA recognition. Proc Natl Acad Sci USA 95:13720–1375

    PubMed  CAS  Google Scholar 

  • Kalousova A, Benes V, Paces J, Paces V, Kozmik Z (1999) DNA binding and transactivating properties of the paired and homeobox protein Pax4. Biochem Biophys Res Commun 259:510–518

    PubMed  CAS  Google Scholar 

  • Kim E, Magen A, Ast G (2007) Different levels of alternative splicing among eukaryotes. Nucleic Acids Res 35:125–131

    PubMed  CAS  Google Scholar 

  • Kopelman NM, Lancet D, Yanai I (2005) Alternative splicing and gene duplication are inversely correlated evolutionary mechanisms. Nat Genet 37:588–589

    PubMed  CAS  Google Scholar 

  • Kozmik Z, Kurzbauer R, Dorfler P, Busslinger M (1993) Alternative splicing of Pax-8 gene transcripts is developmentally regulated and generates isoforms with different transactivation properties. Mol Cell Biol 13:6024–6035

    PubMed  CAS  Google Scholar 

  • Kozmik Z, Czerny T, Busslinger M (1997) Alternatively spliced insertions in the paired domain restrict the DNA sequence specificity of Pax6 and Pax8. EMBO J 16:6793–6803

    PubMed  CAS  Google Scholar 

  • Kozmik Z, Holland ND, Kalousova A, Paces J, Schubert M, Holland LZ (1999) Characterization of an amphioxus paired box gene, AmphiPax2/5/8: developmental expression patterns in optic support cells, nephridium, thyroid-like structures and pharyngeal gill slits, but not in the midbrain-hindbrain boundary region. Development 126:1295–1304

    PubMed  CAS  Google Scholar 

  • Kreslova J, Holland LZ, Schubert M, Burgtorf C, Benes V, Kozmik Z (2002) Functional equivalency of amphioxus and vertebrate Pax258 transcription factors suggests that the activation of mid-hindbrain specific genes in vertebrates occurs via the recruitment of Pax regulatory elements. Gene 282:143–150

    CAS  Google Scholar 

  • Kwak SJ, Vemaraju S, Moorman SJ, Zeddies D, Popper AN, Riley BB (2006) Zebrafish pax5 regulates development of the utricular macula and vestibular function. Dev Dyn 235:3026–3038

    PubMed  Google Scholar 

  • Lamey TM, Koenders A, Ziman M (2004) Pax genes in myogenesis: alternate transcripts add complexity. Histol Histopathol 19:1289–1300

    PubMed  CAS  Google Scholar 

  • Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W, Funke R, Gage D, Harris K, Heaford A, Howland J, Kann L, Lehoczky J, LeVine R, McEwan P, McKernan K, Meldrim J, Mesirov JP, Miranda C, Morris W, Naylor J, Raymond C, Rosetti M, Santos R, Sheridan A, Sougnez C, Stange-Thomann N, Stojanovic N, Subramanian A, Wyman D, Rogers J, Sulston J, Ainscough R, Beck S, Bentley D, Burton J, Clee C, Carter N, Coulson A, Deadman R, Deloukas P, Dunham A, Dunham I, Durbin R, French L, Grafham D, Gregory S, Hubbard T, Humphray S, Hunt A, Jones M, Lloyd C, McMurray A, Matthews L, Mercer S, Milne S, Mullikin JC, Mungall A, Plumb R, Ross M, Shownkeen R, Sims S, Waterston RH, Wilson RK, Hillier LW, McPherson JD, Marra MA, Mardis ER, Fulton LA, Chinwalla AT, Pepin KH, Gish WR, Chissoe SL, Wendl MC, Delehaunty KD, Miner TL, Delehaunty A, Kramer JB, Cook LL, Fulton RS, Johnson DL, Minx PJ, Clifton SW, Hawkins T, Branscomb E, Predki P, Richardson P, Wenning S, Slezak T, Doggett N, Cheng JF, Olsen A, Lucas S, Elkin C, Uberbacher E, Frazier M et al (2001) Initial sequencing and analysis of the human genome. Nature 409:860–921

    PubMed  CAS  Google Scholar 

  • Lejeune F, Maquat LE (2005) Mechanistic links between nonsense-mediated mRNA decay and pre-mRNA splicing in mammalian cells. Curr Opin Cell Biol 17:309–315

    PubMed  CAS  Google Scholar 

  • Lowen M, Scott G, Zwollo P (2001) Functional analyses of two alternative isoforms of the transcription factor Pax-5. J Biol Chem 276:42565–42574

    PubMed  CAS  Google Scholar 

  • Mackereth MD, Kwak SJ, Fritz A, Riley BB (2005) Zebrafish pax8 is required for otic placode induction and plays a redundant role with Pax2 genes in the maintenance of the otic placode. Development 132:371–382

    PubMed  CAS  Google Scholar 

  • MacLean DW, Meedel TH, Hastings KE (1997) Tissue-specific alternative splicing of ascidian troponin I isoforms. Redesign of a protein isoform-generating mechanism during chordate evolution. J Biol Chem 272:32115–32120

    PubMed  CAS  Google Scholar 

  • Matus DQ, Pang K, Daly M, Martindale MQ (2007) Expression of Pax gene family members in the anthozoan cnidarian, Nematostella vectensis. Evol Dev 9:25–38

    PubMed  CAS  Google Scholar 

  • Mikkola I, Bruun JA, Bjorkoy G, Holm T, Johansen T (1999) Phosphorylation of the transactivation domain of Pax6 by extracellular signal-regulated kinase and p38 mitogen-activated protein kinase. J Biol Chem 274:15115–15126

    PubMed  CAS  Google Scholar 

  • Mikkola I, Bruun JA, Holm T, Johansen T (2001) Superactivation of Pax6-mediated transactivation from paired domain-binding sites by dna-independent recruitment of different homeodomain proteins. J Biol Chem 276:4109–4118

    PubMed  CAS  Google Scholar 

  • Mishra R, Gorlov IP, Chao LY, Singh S, Saunders GF (2002) PAX6, paired domain influences sequence recognition by the homeodomain. J Biol Chem 277:49488–49494

    PubMed  CAS  Google Scholar 

  • Miyamoto T, Kakizawa T, Ichikawa K, Nishio S, Kajikawa S, Hashizume K (2001) Expression of dominant negative form of PAX4 in human insulinoma. Biochem Biophys Res Commun 282:34–40

    PubMed  CAS  Google Scholar 

  • Nornes S, Mikkola I, Krauss S, Delghandi M, Perander M, Johansen T (1996) Zebrafish Pax9 encodes two proteins with distinct C-terminal transactivating domains of different potency negatively regulated by adjacent N-terminal sequences. J Biol Chem 271:26914–26923

    PubMed  CAS  Google Scholar 

  • Ogasawara M, Wada H, Peters H, Satoh N (1999) Developmental expression of Pax1/9 genes in urochordate and hemichordate gills: insight into function and evolution of the pharyngeal epithelium. Development 126:2539–2550

    PubMed  CAS  Google Scholar 

  • Oppezzo P, Dumas G, Lalanne AI, Payelle-Brogard B, Magnac C, Pritsch O, Dighiero G, Vuillier F (2005) Different isoforms of BSAP regulate expression of AID in normal and chronic lymphocytic leukemia B cells. Blood 105:2495–503

    PubMed  CAS  Google Scholar 

  • Pan Q, Saltzman AL, Kim YK, Misquitta C, Shai O, Maquat LE, Frey BJ, Blencowe BJ (2006) Quantitative microarray profiling provides evidence against widespread coupling of alternative splicing with nonsense-mediated mRNA decay to control gene expression. Genes Dev 20:153–158

    PubMed  CAS  Google Scholar 

  • Panopoulou G, Hennig S, Groth D, Krause A, Poustka AJ, Herwig R, Vingron M, Lehrach H (2003) New evidence for genome-wide duplications at the origin of vertebrates using an amphioxus gene set and completed animal genomes. Genome Res 13:1056–1066

    PubMed  Google Scholar 

  • Parker CJ, Shawcross SG, Li H, Wang QY, Herrington CS, Kumar S, MacKie RM, Prime W, Rennie IG, Sisley K, Kumar P (2004) Expression of PAX 3 alternatively spliced transcripts and identification of two new isoforms in human tumors of neural crest origin. Int J Cancer 108:314–320

    PubMed  CAS  Google Scholar 

  • Pellizzari L, Tell G, Damante G (1999) Co-operation between the PAI and RED subdomains of Pax-8 in the interaction with the thyroglobulin promoter. Biochem J 337(Pt 2):253–262

    PubMed  CAS  Google Scholar 

  • Pellizzari L, Puppin C, Mariuzzi L, Saro F, Pandolfi M, Di Lauro R, Beltrami CA, Damante G (2006) PAX8 expression in human bladder cancer. Oncol Rep 16:1015–1020

    PubMed  CAS  Google Scholar 

  • Philippe H, Lartillot N, Brinkmann H (2005) Multigene analyses of bilaterian animals corroborate the monophyly of Ecdysozoa, Lophotrochozoa, and Protostomia. Mol Biol Evol 22:1246–1253

    PubMed  CAS  Google Scholar 

  • Poleev A, Wendler F, Fickenscher H, Zannini MS, Yaginuma K, Abbott C, Plachov D (1995) Distinct functional properties of three human paired-box-protein, PAX8, isoforms generated by alternative splicing in thyroid, kidney and Wilms’ tumors. Eur J Biochem 228:899–911

    PubMed  CAS  Google Scholar 

  • Puschel AW, Gruss P, Westerfield M (1992) Sequence and expression pattern of pax-6 are highly conserved between zebrafish and mice. Development 114:643–651

    PubMed  CAS  Google Scholar 

  • Putnam NH, Srivastava M, Hellsten U, Dirks B, Chapman J, Salamov A, Terry A, Shapiro H, Lindquist E, Kapitonov VV, Jurka J, Genikhovich G, Grigoriev IV, Lucas SM, Steele RE, Finnerty JR, Technau U, Martindale MQ, Rokhsar DS (2007) Sea anemone genome reveals ancestral eumetazoan gene repertoire and genomic organization. Science 317:86–94

    PubMed  CAS  Google Scholar 

  • Putnam NH, Butts T, Ferrier DEK, Furlong RF, Hellsten U, Kawashima T, Robinson-Rechavi M, Shoguchi E, Terry A, Yu JK, Benito-Gutiérrez E, Dubchak I, Garcia-Fernàndez J, Grigoriev IV, Horton AC, de Jong PJ, Jurka J, Kapitonov V, Kohara Y, Kuroki Y, Lindquist E, Lucas S, Osoegawa K, Pennacchio LA, Salamov AA, Satou Y, Sauka-Spengler T, Schmutz J, Shin-I T, Toyoda A, Gibson-Brown JJ, Bronner-Fraser M, Fujiyama A, Holland LZ, Holland PWH, Satoh N, Rokhsar DS (2008) The amphioxus genome and the evolution of the chordate karyotype. Nature (in press)

  • Ritz-Laser B, Estreicher A, Gauthier B, Philippe J (2000) The paired homeodomain transcription factor Pax-2 is expressed in the endocrine pancreas and transactivates the glucagon gene promoter. J Biol Chem 275:32708–32715

    PubMed  CAS  Google Scholar 

  • Robichaud GA, Nardini M, Laflamme M, Cuperlovic-Culf M, Ouellette RJ (2004) Human Pax-5 C-terminal isoforms possess distinct transactivation properties and are differentially modulated in normal and malignant B cells. J Biol Chem 279:49956–49963

    PubMed  CAS  Google Scholar 

  • Robinson-Rechavi M, Boussau B, Laudet V (2004) Phylogenetic dating and characterization of gene duplications in vertebrates: the cartilaginous fish reference. Mol Biol Evol 21:580–586

    PubMed  CAS  Google Scholar 

  • Robson EJ, He SJ, Eccles MR (2006) A PANorama of PAX genes in cancer and development. Natl Rev Cancer 6:52–62

    CAS  Google Scholar 

  • Schäfer BW, Czerny T, Bernasconi M, Genini M, Busslinger M (1994) Molecular cloning and characterization of a human PAX-7 cDNA expressed in normal and neoplastic myocytes. Nucleic Acids Res 22:4574–4582

    PubMed  Google Scholar 

  • Sekine R, Kitamura T, Tsuji T, Tojo A (2007) Identification and comparative analysis of Pax5 C-terminal isoforms expressed in human cord blood-derived B cell progenitors. Immunol Lett 111:21–25

    PubMed  CAS  Google Scholar 

  • Seo HC, Saetre BO, Havik B, Ellingsen S, Fjose A (1998) The zebrafish Pax3 and Pax7 homologues are highly conserved, encode multiple isoforms and show dynamic segment-like expression in the developing brain. Mech Dev 70:49–63

    PubMed  CAS  Google Scholar 

  • Shimeld SM, Holland PW (2000) Vertebrate innovations. Proc Natl Acad Sci USA 97:4449–4552

    PubMed  CAS  Google Scholar 

  • Shu DG, Luo HL, Morris SC, Zhang XL, Hu SX, Chen L, Han J, Zhu M, Li Y, Chen LZ (1999) Lower Cambrian vertebrates from South China. Nature 402:42–46

    CAS  Google Scholar 

  • Singh S, Chao LY, Mishra R, Davies J, Saunders GF (2001) Missense mutation at the C-terminus of PAX6 negatively modulates homeodomain function. Hum Mol Genet 10:911–918

    PubMed  CAS  Google Scholar 

  • Singh S, Mishra R, Arango NA, Deng JM, Behringer RR, Saunders GF (2002) Iris hypoplasia in mice that lack the alternatively spliced Pax6(5a) isoform. Proc Natl Acad Sci USA 99:6812–6815

    PubMed  CAS  Google Scholar 

  • Sorek R, Shamir R, Ast G (2004) How prevalent is functional alternative splicing in the human genome? Trends Genet 20:68–71

    PubMed  CAS  Google Scholar 

  • Stamm S, Riethoven JJ, Le Texier V, Gopalakrishnan C, Kumanduri V, Tang Y, Barbosa-Morais NL, Thanaraj TA (2006) ASD: a bioinformatics resource on alternative splicing. Nucleic Acids Res 34:D46–D55

    PubMed  CAS  Google Scholar 

  • Su Z, Wang J, Yu J, Huang X, Gu X (2006) Evolution of alternative splicing after gene duplication. Genome Res 16:182–189

    PubMed  CAS  Google Scholar 

  • Sugnet CW, Kent WJ, Ares M, Jr, Haussler D (2004) Transcriptome and genome conservation of alternative splicing events in humans and mice. Pacif Symp Biocomput 9:66–77

    Google Scholar 

  • Talavera D, Vogel C, Orozco M, Teichmann SA, de la Cruz X (2007) The (in)dependence of alternative splicing and gene duplication. PLoS Comput Biol 3:e33

    PubMed  Google Scholar 

  • Tang HK, Singh S, Saunders GF (1998) Dissection of the transactivation function of the transcription factor encoded by the eye developmental gene PAX6. J Biol Chem 273:7210–7221

    PubMed  CAS  Google Scholar 

  • Tao T, Wasson J, Bernal-Mizrachi E, Behn PS, Chayen S, Duprat L, Meyer J, Glaser B, Permutt MA (1998) Isolation and characterization of the human PAX4 gene. Diabetes 47:1650–1653

    PubMed  CAS  Google Scholar 

  • Tavassoli K, Ruger W, Horst J (1997) Alternative splicing in PAX2 generates a new reading frame and an extended conserved coding region at the carboxy terminus. Hum Genet 101:371–375

    PubMed  CAS  Google Scholar 

  • Thanaraj TA, Stamm S, Clark F, Riethoven JJ, Le Texier V, Muilu J (2004) ASD: the alternative splicing database. Nucleic Acids Res 32:D64–D69

    PubMed  CAS  Google Scholar 

  • Tokuyama Y, Yagui K, Sakurai K, Hashimoto N, Saito Y, Kanatsuka A (1998) Molecular cloning of rat Pax4: identification of four isoforms in rat insulinoma cells. Biochem Biophys Res Commun 248:153–156

    PubMed  CAS  Google Scholar 

  • Tsukamoto K, Nakamura Y, Niikawa N (1994) Isolation of two isoforms of the PAX3 gene transcripts and their tissue-specific alternative expression in human adult tissues. Hum Genet 93:270–274

    PubMed  CAS  Google Scholar 

  • Vorobyov E, Horst J (2004) Expression of two protein isoforms of PAX7 is controlled by competing cleavage-polyadenylation and splicing. Gene 342:107–112

    PubMed  CAS  Google Scholar 

  • Vorobyov E, Horst J (2006) Getting the proto-Pax by the tail. J Mol Evol 63:153–164

    PubMed  CAS  Google Scholar 

  • Wang Q, Kumar S, Slevin M, Kumar P (2006) Functional analysis of alternative isoforms of the transcription factor PAX3 in melanocytes in vitro. Cancer Res 66:8574–8580

    PubMed  CAS  Google Scholar 

  • Wang Q, Kumar S, Mitsios N, Slevin M, Kumar P (2007) Investigation of downstream target genes of PAX3c, PAX3e and PAX3g isoforms in melanocytes by microarray analysis. Int J Cancer 120:1223–1231

    PubMed  CAS  Google Scholar 

  • Ward TA, Nebel A, Reeve AE, Eccles MR (1994) Alternative messenger RNA forms and open reading frames within an additional conserved region of the human PAX-2 gene. Cell Growth Differ 5:1015–1021

    PubMed  CAS  Google Scholar 

  • Waterston RH, Lindblad-Toh K, Birney E, Rogers J, Abril JF, Agarwal P, Agarwala R, Ainscough R, Alexandersson M, An P, Antonarakis SE, Attwood J, Baertsch R, Bailey J, Barlow K, Beck S, Berry E, Birren B, Bloom T, Bork P, Botcherby M, Bray N, Brent MR, Brown DG, Brown SD, Bult C, Burton J, Butler J, Campbell RD, Carninci P, Cawley S, Chiaromonte F, Chinwalla AT, Church DM, Clamp M, Clee C, Collins FS, Cook LL, Copley RR, Coulson A, Couronne O, Cuff J, Curwen V, Cutts T, Daly M, David R, Davies J, Delehaunty KD, Deri J, Dermitzakis ET, Dewey C, Dickens NJ, Diekhans M, Dodge S, Dubchak I, Dunn DM, Eddy SR, Elnitski L, Emes RD, Eswara P, Eyras E, Felsenfeld A, Fewell GA, Flicek P, Foley K, Frankel WN, Fulton LA, Fulton RS, Furey TS, Gage D, Gibbs RA, Glusman G, Gnerre S, Goldman N, Goodstadt L, Grafham D, Graves TA, Green ED, Gregory S, Guigo R, Guyer M, Hardison RC, Haussler D, Hayashizaki Y, Hillier LW, Hinrichs A, Hlavina W, Holzer T, Hsu F, Hua A, Hubbard T, Hunt A, Jackson I, Jaffe DB, Johnson LS, Jones M, Jones TA, Joy A, Kamal M, Karlsson EK et al (2002) Initial sequencing and comparative analysis of the mouse genome. Nature 420:520–562

    PubMed  CAS  Google Scholar 

  • Xu W, Rould MA, Jun S, Desplan C, Pabo CO (1995) Crystal structure of a paired domain-DNA complex at 2.5 A resolution reveals structural basis for Pax developmental mutations. Cell 80:639–650

    PubMed  CAS  Google Scholar 

  • Zhang Y, Emmons SW (1995) Specification of sense-organ identity by a Caenorhabditis elegans Pax-6 homologue. Nature 377:55–59

    PubMed  CAS  Google Scholar 

  • Zwollo P, Arrieta H, Ede K, Molinder K, Desiderio S, Pollock R (1997) The Pax-5 gene is alternatively spliced during B-cell development. J Biol Chem 272:10160–10168

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We would like to thank John Lawrence for his hospitality at the University of South Florida. We also thank Zbynek Kozmik, Christine Beardsley, and Colin Sharpe for helpful criticism and comments on the manuscript. This work was supported by Grant MCB06-20019 from the National Science Foundation to L.Z.H.

Author information

Authors and Affiliations

  1. Marine Biology Research Division, Scripps Institution of Oceanography, La Jolla, CA, 92093-0202, USA

    Stephen Short & Linda Z. Holland

Authors
  1. Stephen Short
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Linda Z. Holland
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Linda Z. Holland.

Electronic supplementary material

Below is the link to the electronic supplementary material.

(DOC 152 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Short, S., Holland, L.Z. The Evolution of Alternative Splicing in the Pax Family: The View from the Basal Chordate Amphioxus. J Mol Evol 66, 605–620 (2008). https://doi.org/10.1007/s00239-008-9113-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00239-008-9113-5

Keywords

Search

Navigation