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

Article

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.

Keywords

Pax Alternative splicing Amphioxus Branchiostoma Gene duplication 

Supplementary material

239_2008_9113_MOESM1_ESM.doc (152 kb)
(DOC 152 kb)

References

  1. 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 166:2617–2626PubMedGoogle Scholar
  2. 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 14:735–745PubMedGoogle Scholar
  3. Balczarek KA, Lai ZC, Kumar S (1997) Evolution of functional diversification of the paired box (Pax) DNA-binding domains. Mol Biol Evol 14:829–842PubMedGoogle Scholar
  4. 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 48:2503–2509PubMedGoogle Scholar
  5. Barber TD, Barber MC, Cloutier TE, Friedman TB (1999) PAX3 gene structure, alternative splicing and evolution. Gene 237:311–319PubMedGoogle Scholar
  6. 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 59:5443–5448PubMedGoogle Scholar
  7. Blair JE, Hedges SB (2005) Molecular phylogeny and divergence times of deuterostome animals. Mol Biol Evol 22:2275–22784PubMedGoogle Scholar
  8. Blencowe BJ (2006) Alternative splicing: new insights from global analyses. Cell 126:37–47PubMedGoogle Scholar
  9. Borson ND, Lacy MQ, Wettstein PJ (2002) Altered mRNA expression of Pax5 and Blimp-1 in B cells in multiple myeloma. Blood 100:4629–4639PubMedGoogle Scholar
  10. 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 444:85–88PubMedGoogle Scholar
  11. 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 33:2661–2675PubMedGoogle Scholar
  12. 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 13:7257–7266PubMedGoogle Scholar
  13. Chalepakis G, Jones FS, Edelman GM, Gruss P (1994) Pax-3 contains domains for transcription activation and transcription inhibition. Proc Natl Acad Sci USA 91:12745–12749PubMedGoogle Scholar
  14. Chi N, Epstein JA (2002) Getting your Pax straight: pax proteins in development and disease. Trends Genet 18:41–47PubMedGoogle Scholar
  15. Conti E, Izaurralde E (2005) Nonsense-mediated mRNA decay: molecular insights and mechanistic variations across species. Curr Opin Cell Biol 17:316–325PubMedGoogle Scholar
  16. 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 15:2858–2871PubMedGoogle Scholar
  17. 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 7:2048–2061PubMedGoogle Scholar
  18. 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 33:4276–4284Google Scholar
  19. 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 15:1971–1982PubMedGoogle Scholar
  20. Eberhard D, Jimenez G, Heavey B, Busslinger M (2000) Transcriptional repression by Pax5 (BSAP) through interaction with corepressors of the Groucho family. EMBO J 19:2292–2303PubMedGoogle Scholar
  21. 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 269:8355–8361PubMedGoogle Scholar
  22. 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 19:8281–8291PubMedGoogle Scholar
  23. 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 125:2701–2710PubMedGoogle Scholar
  24. Gorlov IP, Saunders GF (2002) A method for isolating alternatively spliced isoforms: isolation of murine Pax6 isoforms. Anal Biochem 308:401–404PubMedGoogle Scholar
  25. Graveley BR (2001) Alternative splicing: increasing diversity in the proteomic world. Trends Genet 17:100–107PubMedGoogle Scholar
  26. Hanson IM, Seawright A, Hardman K, Hodgson S, Zaletayev D, Fekete G, van Heyningen V (1993) PAX6 mutations in aniridia. Hum Mol Genet 2:915–920PubMedGoogle Scholar
  27. Heller N, Brändli AW (1997) Xenopus Pax-2 displays multiple splice forms during embryogenesis and pronephric kidney development. Mech Dev 69:83–104PubMedGoogle Scholar
  28. 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 24:208–219PubMedGoogle Scholar
  29. Hetzer-Egger C, Schorpp M, Boehm T (2000) Evolutionary conservation of gene structures of the Pax1/9 gene family. Biochim Biophys Acta 1492:517–521PubMedGoogle Scholar
  30. Holland PW (2003) More genes in vertebrates? J Struct Funct Genomics 3:75–84PubMedGoogle Scholar
  31. Holland LZ, Yu JK (2004) Cephalochordate (amphioxus) embryos: procurement, culture, and basic methods. Methods Cell Biol 74:195–215PubMedCrossRefGoogle Scholar
  32. 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 4:206–214PubMedGoogle Scholar
  33. 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 1:153–165PubMedGoogle Scholar
  34. Holland LZ, Laudet V, Schubert M (2004) The chordate amphioxus: an emerging model organism for developmental biology. Cell Mol Life Sci 61:2290–2308PubMedGoogle Scholar
  35. 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 581:1639–1643PubMedGoogle Scholar
  36. 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 243:628–633PubMedGoogle Scholar
  37. 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 240:196–202PubMedGoogle Scholar
  38. Jun S, Desplan C (1996) Cooperative interactions between paired domain and homeodomain. Development 122:2639–2650PubMedGoogle Scholar
  39. 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 95:13720–1375PubMedGoogle Scholar
  40. 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 259:510–518PubMedGoogle Scholar
  41. Kim E, Magen A, Ast G (2007) Different levels of alternative splicing among eukaryotes. Nucleic Acids Res 35:125–131PubMedGoogle Scholar
  42. Kopelman NM, Lancet D, Yanai I (2005) Alternative splicing and gene duplication are inversely correlated evolutionary mechanisms. Nat Genet 37:588–589PubMedGoogle Scholar
  43. 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 13:6024–6035PubMedGoogle Scholar
  44. 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 16:6793–6803PubMedGoogle Scholar
  45. 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 126:1295–1304PubMedGoogle Scholar
  46. 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 282:143–150Google Scholar
  47. 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 235:3026–3038PubMedGoogle Scholar
  48. Lamey TM, Koenders A, Ziman M (2004) Pax genes in myogenesis: alternate transcripts add complexity. Histol Histopathol 19:1289–1300PubMedGoogle Scholar
  49. 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 409:860–921PubMedGoogle Scholar
  50. Lejeune F, Maquat LE (2005) Mechanistic links between nonsense-mediated mRNA decay and pre-mRNA splicing in mammalian cells. Curr Opin Cell Biol 17:309–315PubMedGoogle Scholar
  51. Lowen M, Scott G, Zwollo P (2001) Functional analyses of two alternative isoforms of the transcription factor Pax-5. J Biol Chem 276:42565–42574PubMedGoogle Scholar
  52. 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 132:371–382PubMedGoogle Scholar
  53. 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 272:32115–32120PubMedGoogle Scholar
  54. Matus DQ, Pang K, Daly M, Martindale MQ (2007) Expression of Pax gene family members in the anthozoan cnidarian, Nematostella vectensis. Evol Dev 9:25–38PubMedGoogle Scholar
  55. 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 274:15115–15126PubMedGoogle Scholar
  56. 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 276:4109–4118PubMedGoogle Scholar
  57. Mishra R, Gorlov IP, Chao LY, Singh S, Saunders GF (2002) PAX6, paired domain influences sequence recognition by the homeodomain. J Biol Chem 277:49488–49494PubMedGoogle Scholar
  58. 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 282:34–40PubMedGoogle Scholar
  59. 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 271:26914–26923PubMedGoogle Scholar
  60. 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 126:2539–2550PubMedGoogle Scholar
  61. 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 105:2495–503PubMedGoogle Scholar
  62. 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 20:153–158PubMedGoogle Scholar
  63. 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 13:1056–1066PubMedGoogle Scholar
  64. 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 108:314–320PubMedGoogle Scholar
  65. 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):253–262PubMedGoogle Scholar
  66. 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 16:1015–1020PubMedGoogle Scholar
  67. Philippe H, Lartillot N, Brinkmann H (2005) Multigene analyses of bilaterian animals corroborate the monophyly of Ecdysozoa, Lophotrochozoa, and Protostomia. Mol Biol Evol 22:1246–1253PubMedGoogle Scholar
  68. 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 228:899–911PubMedGoogle Scholar
  69. Puschel AW, Gruss P, Westerfield M (1992) Sequence and expression pattern of pax-6 are highly conserved between zebrafish and mice. Development 114:643–651PubMedGoogle Scholar
  70. 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 317:86–94PubMedGoogle Scholar
  71. 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)Google Scholar
  72. 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 275:32708–32715PubMedGoogle Scholar
  73. 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 279:49956–49963PubMedGoogle Scholar
  74. Robinson-Rechavi M, Boussau B, Laudet V (2004) Phylogenetic dating and characterization of gene duplications in vertebrates: the cartilaginous fish reference. Mol Biol Evol 21:580–586PubMedGoogle Scholar
  75. Robson EJ, He SJ, Eccles MR (2006) A PANorama of PAX genes in cancer and development. Natl Rev Cancer 6:52–62Google Scholar
  76. 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 22:4574–4582PubMedGoogle Scholar
  77. 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 111:21–25PubMedGoogle Scholar
  78. 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 70:49–63PubMedGoogle Scholar
  79. Shimeld SM, Holland PW (2000) Vertebrate innovations. Proc Natl Acad Sci USA 97:4449–4552PubMedGoogle Scholar
  80. 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 402:42–46Google Scholar
  81. 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 10:911–918PubMedGoogle Scholar
  82. 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 99:6812–6815PubMedGoogle Scholar
  83. Sorek R, Shamir R, Ast G (2004) How prevalent is functional alternative splicing in the human genome? Trends Genet 20:68–71PubMedGoogle Scholar
  84. 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–D55PubMedGoogle Scholar
  85. Su Z, Wang J, Yu J, Huang X, Gu X (2006) Evolution of alternative splicing after gene duplication. Genome Res 16:182–189PubMedGoogle Scholar
  86. 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 9:66–77Google Scholar
  87. 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:e33PubMedGoogle Scholar
  88. 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 273:7210–7221PubMedGoogle Scholar
  89. 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 47:1650–1653PubMedGoogle Scholar
  90. 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 101:371–375PubMedGoogle Scholar
  91. Thanaraj TA, Stamm S, Clark F, Riethoven JJ, Le Texier V, Muilu J (2004) ASD: the alternative splicing database. Nucleic Acids Res 32:D64–D69PubMedGoogle Scholar
  92. 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 248:153–156PubMedGoogle Scholar
  93. 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 93:270–274PubMedGoogle Scholar
  94. Vorobyov E, Horst J (2004) Expression of two protein isoforms of PAX7 is controlled by competing cleavage-polyadenylation and splicing. Gene 342:107–112PubMedGoogle Scholar
  95. Vorobyov E, Horst J (2006) Getting the proto-Pax by the tail. J Mol Evol 63:153–164PubMedGoogle Scholar
  96. 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 66:8574–8580PubMedGoogle Scholar
  97. 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 120:1223–1231PubMedGoogle Scholar
  98. 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 5:1015–1021PubMedGoogle Scholar
  99. 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 420:520–562PubMedGoogle Scholar
  100. 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 80:639–650PubMedGoogle Scholar
  101. Zhang Y, Emmons SW (1995) Specification of sense-organ identity by a Caenorhabditis elegans Pax-6 homologue. Nature 377:55–59PubMedGoogle Scholar
  102. 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 272:10160–10168PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.Marine Biology Research DivisionScripps Institution of OceanographyLa JollaUSA

Personalised recommendations