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Gene Review

OTX2  -  orthodenticle homeobox 2

Homo sapiens

Synonyms: CPHD6, Homeobox protein OTX2, MCOPS5, Orthodenticle homolog 2
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Disease relevance of OTX2


High impact information on OTX2

  • Otx2 and Gbx2 can repress the expression of each other and contribute to the formation of the posterior border of the tectum [4].
  • It is proposed that the brain vesicle that expresses Otx2, Pax2 and En1 might differentiate into the tectum [4].
  • Mis-expression of Otx2 in the metencephalon changed the fate of its alar plate to the tectum [4].
  • These YY1 binding sites are highly conserved in AN enhancers in tetrapods, coelacanth and skate, suggesting that establishment of the YY1 regulation coincides with that of OTX2 function in AN development in an ancestral gnathostome [5].
  • Four additional families display complex inheritance patterns, suggesting that OTX2 mutations alone may not lead to consistent phenotypes [1].

Chemical compound and disease context of OTX2


Biological context of OTX2

  • Therefore, OTX2 may regulate RPE-specific target genes, such as DCT, thereby maintaining the homeostasis of RPE [3].
  • Gene expression analyses showed that OTX2 transcripts were present at high levels in 14 of 15 (93%) medulloblastomas with anaplastic histopathologic features [6].
  • This developmental role is consistent with the evidence suggesting that OTX2 is a medulloblastoma oncogene [2].
  • The three genes and a predicted open reading frame flanking OTX2 in the 14q amplicon were not amplified in at least one of the other nine amplicons, implicating OTX2 as the gene target conferring a selective advantage [2].
  • Surprisingly, analysis of only five genomes revealed novel amplicons on chromosome 14q, one of which contained the orthodenticle homologue 2 (OTX2) homeobox gene [2].

Anatomical context of OTX2

  • DNA copy number analysis showed that OTX2 had undergone genomic amplification in 2 of 11 medulloblastoma cell lines and 8 of 42 primary tumors [2].
  • Serial analysis of gene expression of 240 different human tumors or normal tissues revealed that 96% of all 783 OTX2 transcripts sequenced were in medulloblastomas or embryonic stem cells [2].
  • Direct interactions of OTX2 with LIM1 or HNF-3beta may play important roles in anterior visceral endoderm and/or anterior mesendoderm to constitute transcriptional regulatory networks for head development [7].
  • By cotransfecting HeLa cells, OTX2 could transactivate the irbp promoter [8].
  • OTX2 activates the molecular network underlying retina pigment epithelium differentiation [9].

Associations of OTX2 with chemical compounds

  • OTX2 homeodomain protein binds a DNA element necessary for interphotoreceptor retinoid binding protein gene expression [10].
  • Different combinations of signals are responsible for different aspects of this early transient induction: FGF initiates expression of Sox3 and ERNI, retinoic acid can induce Cyp26A1 and only a combination of low levels of FGF8 together with Wnt- and BMP-antagonists can induce Otx2 [11].
  • Our results are consistent with the view that pineal expression of Otx2 is required for development and we hypothesize that it plays a role in the adult in controlling the expression of the cluster of genes associated with phototransduction and melatonin synthesis [12].

Physical interactions of OTX2

  • OTX2 binds to the DCT gene promoter in vivo, as judged by chromatin immunoprecipitation assays [3].
  • The human homeodomain protein OTX2 binds to the human tenascin-C promoter and trans-represses its activity in transfected cells [13].
  • Here we report on the ability of the human homeodomain protein OTX2 to bind with high affinity to a target sequence present in the promoter of the gene encoding the human extracellular matrix protein tenascin-C and to repress its transcriptional activity in transiently transfected cells [13].
  • A novel mutation in OTX2 binds normally to target genes and acts as a dominant negative inhibitor of HESX1 gene expression [14].

Regulatory relationships of OTX2

  • Transient expression assays revealed that OTX2 activated the DCT gene promoter through the OTX-2-binding site in an RPE-specific manner [3].
  • Furthermore, we present evidence that FGF8 can regulate regionalization of the prosencephalon through inhibition of Otx2 and Emx2 expression [15].
  • Here, we have examined cell mingling at the isthmus, where Otx2-expressing midbrain cells abut Gbx2-expressing hindbrain cells [4] [16].

Other interactions of OTX2

  • OTX1 compensates for OTX2 requirement in regionalisation of anterior neuroectoderm [17].
  • However, both CHX10 (14q24.3), mutations of which give rise to CMIC in mouse models, and OTX2 (14q21-22) can be excluded as candidates for autosomal recessive congenital microphthalmia (arCMIC), since they map outside the critical disease region defined by recombination events [18].
  • Using a candidate-gene approach, we have identified heterozygous coding-region changes in the homeobox gene OTX2 in eight families with ocular malformations [1].
  • CRX RT-PCR product from cells transfected with AODNs was greatly diminished following transfection with an AODN whereas control transcripts, including that of OTX2, were relatively unaffected [19].
  • Developmental malformations of the eye: the role of PAX6, SOX2 and OTX2 [20].

Analytical, diagnostic and therapeutic context of OTX2


  1. Heterozygous mutations of OTX2 cause severe ocular malformations. Ragge, N.K., Brown, A.G., Poloschek, C.M., Lorenz, B., Henderson, R.A., Clarke, M.P., Russell-Eggitt, I., Fielder, A., Gerrelli, D., Martinez-Barbera, J.P., Ruddle, P., Hurst, J., Collin, J.R., Salt, A., Cooper, S.T., Thompson, P.J., Sisodiya, S.M., Williamson, K.A., Fitzpatrick, D.R., van Heyningen, V., Hanson, I.M. Am. J. Hum. Genet. (2005) [Pubmed]
  2. Genomic amplification of orthodenticle homologue 2 in medulloblastomas. Boon, K., Eberhart, C.G., Riggins, G.J. Cancer Res. (2005) [Pubmed]
  3. OTX2 regulates expression of DOPAchrome tautomerase in human retinal pigment epithelium. Takeda, K., Yokoyama, S., Yasumoto, K., Saito, H., Udono, T., Takahashi, K., Shibahara, S. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  4. Regionalization of the optic tectum: combinations of gene expression that define the tectum. Nakamura, H. Trends Neurosci. (2001) [Pubmed]
  5. Acetylated YY1 regulates Otx2 expression in anterior neuroectoderm at two cis-sites 90 kb apart. Takasaki, N., Kurokawa, D., Nakayama, R., Nakayama, J., Aizawa, S. EMBO J. (2007) [Pubmed]
  6. Identification of OTX2 as a medulloblastoma oncogene whose product can be targeted by all-trans retinoic acid. Di, C., Liao, S., Adamson, D.C., Parrett, T.J., Broderick, D.K., Shi, Q., Lengauer, C., Cummins, J.M., Velculescu, V.E., Fults, D.W., McLendon, R.E., Bigner, D.D., Yan, H. Cancer Res. (2005) [Pubmed]
  7. OTX2 directly interacts with LIM1 and HNF-3beta. Nakano, T., Murata, T., Matsuo, I., Aizawa, S. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  8. Elements regulating the transcription of human interstitial retinoid-binding protein (IRBP) gene in cultured retinoblastoma cells. Fong, S.L., Fong, W.B. Curr. Eye Res. (1999) [Pubmed]
  9. OTX2 activates the molecular network underlying retina pigment epithelium differentiation. Martínez-Morales, J.R., Dolez, V., Rodrigo, I., Zaccarini, R., Leconte, L., Bovolenta, P., Saule, S. J. Biol. Chem. (2003) [Pubmed]
  10. OTX2 homeodomain protein binds a DNA element necessary for interphotoreceptor retinoid binding protein gene expression. Bobola, N., Briata, P., Ilengo, C., Rosatto, N., Craft, C., Corte, G., Ravazzolo, R. Mech. Dev. (1999) [Pubmed]
  11. A role for the hypoblast (AVE) in the initiation of neural induction, independent of its ability to position the primitive streak. Albazerchi, A., Stern, C.D. Dev. Biol. (2007) [Pubmed]
  12. Expression of the Otx2 homeobox gene in the developing mammalian brain: embryonic and adult expression in the pineal gland. Rath, M.F., Muñoz, E., Ganguly, S., Morin, F., Shi, Q., Klein, D.C., Møller, M. J. Neurochem. (2006) [Pubmed]
  13. The human homeodomain protein OTX2 binds to the human tenascin-C promoter and trans-represses its activity in transfected cells. Gherzi, R., Briata, P., Boncinelli, E., Ponassi, M., Querzè, G., Viti, F., Corte, G., Zardi, L. DNA Cell Biol. (1997) [Pubmed]
  14. A novel dominant negative mutation of OTX2 associated with combined pituitary hormone deficiency. Diaczok, D., Romero, C., Zunich, J., Marshall, I., Radovick, S. J. Clin. Endocrinol. Metab. (2008) [Pubmed]
  15. Coordinate expression of Fgf8, Otx2, Bmp4, and Shh in the rostral prosencephalon during development of the telencephalic and optic vesicles. Crossley, P.H., Martinez, S., Ohkubo, Y., Rubenstein, J.L. Neuroscience (2001) [Pubmed]
  16. Cell mixing between the embryonic midbrain and hindbrain. Jungbluth, S., Larsen, C., Wizenmann, A., Lumsden, A. Curr. Biol. (2001) [Pubmed]
  17. OTX1 compensates for OTX2 requirement in regionalisation of anterior neuroectoderm. Acampora, D., Annino, A., Puelles, E., Alfano, I., Tuorto, F., Simeone, A. Gene Expr. Patterns (2003) [Pubmed]
  18. A locus for autosomal recessive congenital microphthalmia maps to chromosome 14q32. Bessant, D.A., Khaliq, S., Hameed, A., Anwar, K., Mehdi, S.Q., Payne, A.M., Bhattacharya, S.S. Am. J. Hum. Genet. (1998) [Pubmed]
  19. Endogenous CRX expression and IRBP promoter activity in retinoblastoma cells. Boatright, J.H., Borst, D.E., Stodulkova, E., Nickerson, J.M. Brain Res. (2001) [Pubmed]
  20. Developmental malformations of the eye: the role of PAX6, SOX2 and OTX2. Hever, A.M., Williamson, K.A., van Heyningen, V. Clin. Genet. (2006) [Pubmed]
  21. OTX1 and OTX2 expression correlates with the clinicopathologic classification of medulloblastomas. de Haas, T., Oussoren, E., Grajkowska, W., Perek-Polnik, M., Popovic, M., Zadravec-Zaletel, L., Perera, M., Corte, G., Wirths, O., van Sluis, P., Pietsch, T., Troost, D., Baas, F., Versteeg, R., Kool, M. J. Neuropathol. Exp. Neurol. (2006) [Pubmed]
  22. Molecular dissection reveals decreased activity and not dominant negative effect in human OTX2 mutants. Chatelain, G., Fossat, N., Brun, G., Lamonerie, T. J. Mol. Med. (2006) [Pubmed]
  23. Fgf8 and Gbx2 induction concomitant with Otx2 repression is correlated with midbrain-hindbrain fate of caudal prosencephalon. Hidalgo-Sánchez, M., Simeone, A., Alvarado-Mallart, R.M. Development (1999) [Pubmed]
  24. Evolutionary conservation of otd/Otx2 transcription factor action: a genome-wide microarray analysis in Drosophila. Montalta-He, H., Leemans, R., Loop, T., Strahm, M., Certa, U., Primig, M., Acampora, D., Simeone, A., Reichert, H. Genome Biol. (2002) [Pubmed]
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