Orquera, D.P.; de Souza, F.S.J."Evolution of the Rax family of developmental transcription factors in vertebrates" (2017) Mechanisms of Development. 144:163-170
Estamos trabajando para incorporar este artículo al repositorio
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor


Rax proteins comprise a small family of paired-type, homeodomain-containing transcription factors with essential functions in eye and forebrain development. While invertebrates possess only one Rax gene, vertebrates can have several Rax paralogue genes, but the evolutionary history of the members of the family has not been studied in detail. Here, we present a thorough analysis of the evolutionary relationships between vertebrate Rax genes and proteins available in diverse genomic databases. Phylogenetic and synteny analyses indicate that Rax genes went through a duplication in an ancestor of all jawed vertebrates (Gnathostomata), giving rise to the ancestral vertebrate Rax1 and Rax2 genes. This duplication event is likely related to the proposed polyploidisations that occurred during early vertebrate evolution. Subsequent genome-wide duplications in the lineage of ray-finned fish (Actinopterygii) originated new Rax2 paralogues in the genomes of teleosts. In the lobe-finned fish lineage (Sarcopterygii), the N-terminal octapeptide domain of Rax2 was lost in a common ancestor of tetrapods, giving rise to a shorter version of Rax2 in this lineage. Within placental mammals, the Rax2 gene was lost altogether in an ancestor of rodents and lagomorphs (Glires). Finally, we discuss the scientific literature in the light of Rax gene evolution and propose new avenues of research on the function of this important family of transcriptional regulators. © 2016 Elsevier Ireland Ltd


Documento: Artículo
Título:Evolution of the Rax family of developmental transcription factors in vertebrates
Autor:Orquera, D.P.; de Souza, F.S.J.
Filiación:Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, 1428, Argentina
Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, 1428, Argentina
Palabras clave:Eye development; Gene duplication; Hypothalamus; rx1; rx2; rx3; homeodomain protein; homeodomain protein Rax; unclassified drug; homeodomain protein; transcription factor; amino terminal sequence; Article; brain development; cell lineage; developmental biology; forebrain; gene; gene duplication; genetic association; genetic database; molecular evolution; nonhuman; phylogeny; priority journal; Rax gene; Rax1 gene; Rax2 gene; sequence alignment; sequence analysis; synteny; teleost; transcription regulation; animal; genetics; vertebrate; Animals; Evolution, Molecular; Homeodomain Proteins; Phylogeny; Synteny; Transcription Factors; Vertebrates
Página de inicio:163
Página de fin:170
Título revista:Mechanisms of Development
Título revista abreviado:Mech. Dev.
CAS:Homeodomain Proteins; Transcription Factors


  • Abouzeid, H., Youssef, M.A., Bayoumi, N., ElShakankiri, N., Marzouk, I., Hauser, P., Schorderet, D.F., RAX and anophthalmia in humans: evidence of brain anomalies (2012) Mol. Vis., 18, pp. 1449-1456
  • Andreazzoli, M., Gestri, G., Angeloni, D., Menna, E., Barsacchi, G., Role of Xrx1 in Xenopus eye and anterior brain development (1999) Development, 126, pp. 2451-2460
  • Andreazzoli, M., Gestri, G., Cremisi, F., Casarosa, S., Dawid, I.B., Baracchi, G., Xrx1 controls proliferation and neurogenesis in Xenopus anterior neural plate (2003) Development, 130, pp. 5143-5154
  • Arendt, D., Evolution of eyes and photoreceptor cell types (2003) Int. J. Dev. Biol., 47, pp. 563-571
  • Arendt, D., Tessmar-Raible, K., Snyman, H., Dorresteijn, A.W., Wittbrodt, J., Ciliary photoreceptors with a vertebrate-type opsin in an invertebrate brain (2004) Science, 306, pp. 869-871
  • Bailey, T.J., El-Hodiri, H., Zhang, L., Shah, R., Mathers, P.H., Jamrich, M., Regulation of vertebrate eye development by Rx genes (2004) Int J Dev Biol., 48, pp. 761-770
  • Blair, J.E., Hedges, S.B., Molecular phylogeny and divergence times of deuterostome animals (2005) Mol. Biol. Evol., 22, pp. 2275-2284
  • Cañestro, C., Albalat, R., Irimia, M., Garcia-Fernàndez, J., Impact of gene gains, losses and duplication modes on the origin and diversification of vertebrates (2013) Semin. Cell Dev. Biol., 24, pp. 83-94
  • Casarosa, S., Andreazzoli, M., Simeone, A., Barsacchi, G., Xrx1, a novel Xenopushomeobox gene expressed during eye and pineal gland development (1997) Mech. Dev., 61, pp. 187-198
  • Catchen, J.M., Conery, J.S., Postlethwait, J.H., Automated identification of conserved synteny after whole genome duplication (2009) Genome Res., 19, pp. 1497-1505
  • Chen, C.M., Cepko, C.L., The chicken RaxL gene plays a role in the initiation of photoreceptor differentiation (2002) Development, 129, pp. 5363-5375
  • Chevenet, F., Brun, C., Banuls, A.L., Jacq, B., Christen, R., TreeDyn: towards dynamic graphics and annotations for analyses of trees (2006) BMC Biochem., 7, p. 439
  • Chuang, J.C., Raymond, P.A., Zebrafish genes rx1 and rx2 help define the region of forebrain that gives rise to retina (2001) Dev. Biol., 231, pp. 13-30
  • Chuang, J.C., Mathers, P.H., Raymond, P.A., Expression of three Rx homeobox genes in embryonic and adult zebrafish (1999) Mech. Dev., 84, pp. 195-198
  • Clark, K., Karsch-Mizrachi, I., Lipman, D.J., Ostell, J., Sayers, E.W., GenBank (2016) Nucleic Acids Res., 2016 (44), pp. D67-D72
  • D'Aniello, S., D'Aniello, E., Locascio, A., Memoli, A., Corrado, M., Russo, M.T., Aniello, F., Branno, M., The ascidian homolog of the vertebrate homeobox gene Rx is essential for ocellus development and function (2006) Differentiation, 74, pp. 222-234
  • Davis, R.J., Tavsanli, B.C., Dittrich, C., Walldorf, U., Mardon, G., Drosophila retinal homeobox (drx) is not required for establishment of the visual system, but is required for brain and clypeus development (2003) Dev. Biol., 259, pp. 272-287
  • de Souza, F.S., Bumaschny, V.F., Low, M.J., Rubinstein, M., Subfunctionalization of expression and peptide domains following the ancient duplication of the proopiomelanocortin gene in teleost fishes (2005) Mol. Biol. Evol., 22, pp. 2417-2427
  • Deschet, K., Bourrat, F., Ristoratore, F., Chourrout, D., Joly, J.S., Expression of the medaka (Oryzias latipes) Ol-Rx3 paired-like gene in two diencephalic derivatives, the eye and the hypothalamus (1999) Mech. Dev., 83, pp. 179-182
  • Dickmeis, T., Lahiri, K., Nica, G., Vallone, D., Santoriello, C., Neumann, C.J., Hammerschmidt, M., Foulkes, N.S., Glucocorticoids play a key role in circadian cell cycle rhythms (2007) PLoS Biol., 5
  • Eggert, T., Hauck, B., Hildebrandt, N., Gehring, W.J., Walldorf, U., Isolation of a Drosophila homolog of the vertebrate homeobox gene Rx and its possible role in brain and eye development (1998) Proc. Natl. Acad. Sci. U. S. A., 95, pp. 2343-2348
  • Felsenstein, J., Confidence limits on phylogenies: an approach using the bootstrap (1985) Evolution, 39, pp. 783-791
  • Fish, M.B., Nakayama, T., Fisher, M., Hirsch, N., Cox, A., Reeder, R., Carruthers, S., Grainger, R.M., Xenopus mutant reveals necessity of rax for specifying the eye field which otherwise forms tissue with telencephalic and diencephalic character (2014) Dev. Biol., 395, pp. 317-330
  • Flicek, P., Amode, M.R., Barrell, D., Beal, K., Billis, K., Brent, S., Carvalho-Silva, D., Searle, S.M., Ensembl 2014 (2014) Nucleic Acids Res., 42, pp. D749-D755
  • Force, A., Lynch, M., Pickett, F.B., Amores, A., Yan, Y.L., Postlethwait, J., Preservation of duplicate genes by complementary, degenerative mutations (1999) Genetics, 151, pp. 1531-1545
  • Furukawa, T., Kozak, C.A., Cepko, C.L., rax, a novel paired-type homeobox gene, shows expression in the anterior neural fold and developing retina (1997) Proc. Natl. Acad. Sci. USA, 94, pp. 3088-3093
  • Giudetti, G., Giannaccini, M., Biasci, D., Mariotti, S., Degl'innocenti, A., Perrotta, M., Barsacchi, G., Andreazzoli, M., Characterization of the Rx1-dependent transcriptome during early retinal development (2014) Dev. Dyn., 243, pp. 1352-1361
  • Glasauer, S.M., Neuhauss, S.C., Whole-genome duplication in teleost fishes and its evolutionary consequences (2014) Mol. Gen. Genomics., 289, pp. 1045-1060
  • Gonzalez-Rodriguez, J., Pelcastre, E.L., Tovilla-Canales, J.L., Garcia-Ortiz, J.E., Amato-Almanza, M., Villanueva-Mendoza, C., Espinosa-Mattar, Z., Zenteno, J.C., Mutational screening of CHX10, GDF6, OTX2, RAX and SOX2 genes in 50 unrelated microphthalmia-anophthalmia-coloboma (MAC) spectrum cases (2010) Br. J. Ophthalmol., 94, pp. 1100-1104
  • Guindon, S., Dufayard, J.F., Lefort, V., Anisimova, M., Hordijk, W., Gascuel, O., New algorithms and methods to estimate maximum-likelihood phylogenies: assessing the performance of PhyML 3.0 (2010) Syst. Biol., 59, pp. 307-321
  • Howe, K., Clark, M.D., Torroja, C.F., Torrance, J., Berthelot, C., Muffato, M., Collins, J.E., Stemple, D.L., The zebrafish reference genome sequence and its relationship to the human genome (2013) Nature, 496, pp. 498-503
  • Hunnekuhl, V.S., Akam, M., An anterior medial cell population with an apical-organ-like transcriptional profile that pioneers the central nervous system in the centipede Strigamia maritima (2014) Dev. Biol., 396, pp. 136-149
  • Kraft, K.F., Massey, E.M., Kolb, D., Walldorf, U., Urbach, R., Retinal homeobox promotes cell growth, proliferation and survival of mushroom body neuroblasts in the Drosophila brain (2016) Mech. Dev., 142, pp. 50-61
  • Lamb, T.D., Evolution of phototransduction, vertebrate photoreceptors and retina (2013) Prog. Retin. Eye Res., 36, pp. 52-119
  • Larsson, A., AliView: a fast and lightweight alignment viewer and editor for large datasets (2014) Bioinformatics, 30, pp. 3276-3278
  • Le, S.Q., Gascuel, O., An improved general amino acid replacement matrix (2008) Mol. Biol. Evol., 25, pp. 1307-1320
  • Lequeux, L., Rio, M., Vigouroux, A., Titeux, M., Malecaze, F., Chassaing, N., Calvas, P., Confirmation of RAX gene involvement in human anophthalamia (2008) Clin. Genet., 74, pp. 392-395
  • London, N.J., Kessler, P., Williams, B., Pauer, G.J., Hagstrom, S.A., Traboulsi, E.I., Sequence alterations in RX in patients with microphthalmia, anophthalmia, and coloboma (2009) Mol. Vis., 15, pp. 162-167
  • Loosli, F., Staub, W., Finger-Baier, K.C., Ober, E.A., Verkade, H., Wittbrodt, J., Baier, H., Loss of eyes in zebrafish caused by mutation of chokh/rx3 (2003) EMBO Rep., 4, pp. 894-899
  • Loosli, F., Winkler, S., Burgtorf, C., Wurmbach, E., Ansorge, W., Henrich, T., Grabher, C., Wittbrodt, J., Medaka eyeless is the key factor linking retinal determination and eye growth (2001) Development, 128, pp. 4035-4044
  • Lu, F., Kar, D., Gruenig, N., Zhang, Z.W., Cousins, N., Rodgers, H.M., Swindell, E.C., Kurrasch, D.M., Rax is a selector gene for mediobasal hypothalamic cell types (2013) J. Neurosci., 33, pp. 259-272
  • Marlow, H., Tosches, M.A., Tomer, R., Steinmetz, P.R., Lauri, A., Larsson, T., Arendt, D., Larval body patterning and apical organs are conserved in animal evolution (2014) BMC Biol., 12, p. 7
  • Mathers, P.H., Grinberg, A., Mahon, K.A., Jamrich, M., The Rx homeobox gene is essential for vertebrate eye development (1997) Nature, 387, pp. 603-607
  • Mazza, M.E., Pang, K., Reitzel, A.M., Martindale, M.Q., Finnerty, J.R., A conserved cluster of three PRD-class homeobox genes (homeobrain, rx and orthopedia) in the Cnidaria and Protostomia (2010) EvoDevo, 1, p. 3
  • McGaugh, S.E., Gross, J.B., Aken, B., Blin, M., Borowsky, R., Chalopin, D., Hinaux, H., Warren, W.C., The cavefish genome reveals candidate genes for eye loss (2014) Nat. Commun., 5, p. 5307
  • Medina-Martinez, O., Amaya-Manzanares, F., Liu, C., Mendoza, M., Shah, R., Zhang, L., Behringer, R.R., Jamrich, M., Cell-autonomous requirement for rx function in the mammalian retina and posterior pituitary (2009) PLoS One, 4
  • Mehta, T.K., Ravi, V., Yamasaki, S., Lee, A.P., Lian, M.M., Tay, B.H., Tohari, S., Venkatesh, B., Evidence for at least six Hox clusters in the Japanese lamprey (Lethenteron japonicum) (2013) Proc. Natl. Acad. Sci. U. S. A., 110, pp. 16044-16049
  • Muranishi, Y., Terada, K., Furukawa, T., An essential role for Rax in retina and neuroendocrine system development (2012) Develop. Growth Differ., 54, pp. 341-348
  • Muthu, V., Eachus, H., Ellis, P., Brown, S., Placzek, M., Rx3 and Shh direct anisotropic growth and specification in the zebrafish tuberal/anterior hypothalamus (2016) Development, 143, pp. 2651-2663
  • Nelson, S.M., Park, L., Stenkamp, D.L., Retinal homeobox 1 is required for retinal neurogenesis and photoreceptor differentiation in embryonic zebrafish (2009) Dev. Biol., 328, pp. 24-39
  • Ohuchi, H., Tomonari, S., Itoh, H., Mikawa, T., Noji, S., Identification of chick rax/rx genes with overlapping patterns of expression during early eye and brain development (1999) Mech. Dev., 85, pp. 193-195
  • Orquera, D.P., Nasif, S., Low, M.J., Rubinstein, M., de Souza, F.S., Essential function of the transcription factor rax in the early patterning of the mammalian hypothalamus (2016) Dev. Biol., 416, pp. 212-224
  • Pan, Y., Nekkalapudi, S., Kelly, L.E., El-Hodiri, H.M., The Rx-like homeobox gene (Rx-L) is necessary for normal photoreceptor development (2006) Invest. Opthtalmol. Vis. Sci., 47, pp. 4245-4253
  • Panopoulou, G., Poustka, A.J., Timing and mechanism of ancient vertebrate genome duplications – the adventure of a hypothesis (2005) Trends Genet., 21, pp. 559-567
  • Philippe, H., Brinkmann, H., Lavrov, D.V., Littlewood, D.T.J., Manuel, M., Wörheide, G., Baurain, D., Resolving difficult phylogenetic questions: why more sequences are not enough (2011) PLoS Biol., 9
  • Pollet, N., Mazabraud, A., Insights from Xenopus genomes (2006) Genome Dyn., 2, pp. 138-153
  • Putnam, N.H., Butts, T., Ferrier, D.E., Furlong, R.F., Hellsten, U., Kawashima, T., Robinson-Rechavi, M., Rokhsar, D.S., The amphioxus genome and the evolution of the chordate karyotype (2008) Nature, 453, pp. 1064-1071
  • Reinhardt, R., Centanin, L., Tavhelidse, T., Inoue, D., Wittbrodt, B., Concordet, J.P., Martinez-Morales, J.R., Wittbrodt, J., Sox2, Tlx, Gli3, and Her9 converge on Rx2 to define retinal stem cells in vivo (2015) EMBO J., 34, pp. 1572-1588
  • Rojas-Muñoz, A., Dahm, R., Nüsslein-Volhard, C., chokh/rx3 specifies the retinal pigment epithelium fate independently of eye morphogenesis (2005) Dev. Biol., 288, pp. 348-362
  • Rokas, A., Williams, B.L., King, N., Carroll, S.B., Genome-scale approaches to resolving incongruence in molecular phylogenies (2003) Nature, 425, pp. 798-804
  • Sakagami, K., Ishii, A., Shimada, N., Yasuda, K., RaxL regulates chick ganglion cell development (2003) Mech. Dev., 120, pp. 881-895
  • Sasai, Y., Eiraku, M., Suga, H., In vitro organogenesis in three dimensions: self-organising stem cells (2012) Development, 139, pp. 4111-4121
  • Schulte, J.E., O'Brien, C.S., Conte, M.A., O'Quin, K.E., Carleton, K.L., Interspecific variation in Rx1 expression controls opsin expression and causes visual system diversity in African cichlid fishes (2014) Mol. Biol. Evol., 31, pp. 2297-2308
  • Sievers, F., Higgins, D.G., Clustal omega (2014) Curr. Protoc. Bioinformatics., 48, pp. 3.13.1-3.13.16
  • Smith, J.J., Keinath, M.C., The sea lamprey meiotic map improves resolution of ancient vertebrate genome duplications (2015) Genome Res., 25, pp. 1081-1090
  • Smith, J.J., Kuraku, S., Holt, C., Sauka-Spengler, T., Jiang, N., Campbell, M.S., Yandell, M.D., Li, W., Sequencing of the sea lamprey (Petromyzon marinus) genome provides insights into vertebrate evolution (2013) Nat. Genet., 45, pp. 415-421
  • Speir, M.L., Zweig, A.S., Rosenbloom, K.R., Raney, B.J., Paten, B., Nejad, P., Lee, B.T., Kent, W.J., The UCSC genome browser database: 2016 update (2016) Nucleic Acids Res., 44, pp. D717-D725
  • Stigloher, C., Ninkovic, J., Laplante, M., Geling, A., Tannhauser, B., Topp, S., Kikuta, H., Bally-Cuif, L., Segregation of telencephalic and eye-field identities inside the zebrafish forebrain territory is controlled by Rx3 (2006) Development, 133, pp. 2925-2935
  • Swindell, E.C., Liu, C., Shah, R., Smith, A.N., Lang, R.A., Jamrich, M., Eye formation in the absence of retina (2008) Dev. Biol., 322, pp. 56-64
  • Tessmar-Raible, K., Raible, F., Christodoulou, F., Guy, K., Rembold, M., Hausen, H., Arendt, D., Conserved sensory-neurosecretory cell types in annelid and fish forebrain: insights into hypothalamus evolution (2007) Cell, 129, pp. 1389-1400
  • Tucker, P., Laemle, L., Munson, A., Kanekar, S., Oliver, E.R., Brown, N., Schlecht, H., Glaser, T., The eyeless mouse mutation (ey1) removes an alternative start codon from the Rx/rax homeobox gene (2001) Genesis, 31, pp. 43-53
  • Vopalensky, P., Pergner, J., Liegertova, M., Benito-Gutierrez, E., Arendt, D., Kozmik, Z., Molecular analysis of the amphioxus frontal eye unravels the evolutionary origin of the retina and pigment cells of the vertebrate eye (2012) Proc. Natl. Acad. Sci. U. S. A., 109, pp. 15383-15388
  • Voronina, V.A., Kozhemyakina, E.A., O'Kernick, C.M., Kahn, N.D., Wenger, S.L., Linberg, J.V., Schneider, A.S., Mathers, P.H., Mutations in the human RAX homeobox gene in a patient with anophthalamia and sclerocornea (2004) Hum. Mol. Genet., 13, pp. 315-322
  • Wang, Q.L., Chen, S., Esumi, N., Swain, P.K., Haines, H.S., Peng, G., Melia, B.M., Zack, D.J., QRX, a novel homeobox gene, modulates photoreceptor gene expression (2004) Hum. Mol. Genet., 13, pp. 1025-1040
  • Winkler, S., Loosli, F., Henrich, T., Wakamatsu, Y., Wittbrodt, J., The conditional medaka mutation eyeless uncouples patterning and morphogenesis of the eye (2000) Development, 127, pp. 1911-1919
  • Wu, H.Y., Perron, M., Hollemann, T., The role of Xenopus Rx-L in photoreceptor cell determination (2009) Dev. Biol., 327, pp. 352-365
  • Yang, P., Chiang, P.W., Weleber, R.G., Pennesi, M.E., Autosomal dominant retinal dystrophy with electronegative waveform associated with a novel RAX2 mutation (2015) JAMA Ophthalmol, 133, pp. 653-661
  • Yoshida, K., Saiga, H., Repression of Rx gene on the left side of the sensory vesicle by nodal signaling is crucial for right-sided formation of the ocellus photoreceptor in the development of Ciona intestinalis (2011) Dev. Biol., 354, pp. 144-150
  • Zhang, L., Mathers, P.H., Jamrich, M., Function of Rx, but not Pax6, is essential for the formation of retinal progenitor cells in mice (2000) Genesis, 28, pp. 135-142
  • Zhong, Y.F., Holland, P.W., The dynamics of vertebrate homeobox gene evolution: gain and loss of genes in mouse and human lineages (2011) BMC Evol. Biol., 11, p. 169


---------- APA ----------
Orquera, D.P. & de Souza, F.S.J. (2017) . Evolution of the Rax family of developmental transcription factors in vertebrates. Mechanisms of Development, 144, 163-170.
---------- CHICAGO ----------
Orquera, D.P., de Souza, F.S.J. "Evolution of the Rax family of developmental transcription factors in vertebrates" . Mechanisms of Development 144 (2017) : 163-170.
---------- MLA ----------
Orquera, D.P., de Souza, F.S.J. "Evolution of the Rax family of developmental transcription factors in vertebrates" . Mechanisms of Development, vol. 144, 2017, pp. 163-170.
---------- VANCOUVER ----------
Orquera, D.P., de Souza, F.S.J. Evolution of the Rax family of developmental transcription factors in vertebrates. Mech. Dev. 2017;144:163-170.