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Gene Review

SIX3  -  SIX homeobox 3

Homo sapiens

Synonyms: Homeobox protein SIX3, Sine oculis homeobox homolog 3
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Disease relevance of SIX3


High impact information on SIX3

  • Mutational analysis has identified four different mutations in the homeodomain of SIX3 that are predicted to interfere with transcriptional activation and are associated with HPE [5].
  • Gain-of-function studies in medaka show a clear synergistic activity between SIX3/SIX6 and TLE1, which, on its own, can expand the eye field [6].
  • Conversely, AES alone decreases the eye size and abrogates the phenotypic consequences of SIX3/6 over-expression [6].
  • Consistent with the role of Wnts as posteriorizing agents in neural tissue, we found that Wnt signaling was sufficient to induce Irx3 and repress Six3 expression in forebrain explants [7].
  • The position of the zona limitans intrathalamica (zli), a boundary-cell population that develops between the ventral (vT) and dorsal thalamus (dT), is predicted by the apposition of Six3 and Irx3 expression domains [7].

Biological context of SIX3

  • A 2-kb promoter fragment of SIX3, a human transcription factor essential for vertebrate eye development, has been characterized in a gene reporter assay system [8].
  • A number of mutations in different genes have been linked to this malformation, including three missense mutations in the homeodomain of the transcription factor SIX3 [1].
  • We report a case of EMC with no detectable NR4A3 gene alterations, as assessed with various molecular techniques including reverse transcription-polymerase chain reaction (RT-PCR), Southern blotting, interphase fluorescence in situ hybridization, and PCR single-strand conformation polymorphism-but with coexpression of native NOR1 and SIX3 [2].
  • Interestingly, the map position of human SIX3 overlaps the locations of two dominant disorders with ocular phenotypes that have been assigned to this chromosomal region, holoprosencephaly type 2 and Malattia Leventinese [3].
  • SIX3 was mapped to human chromosome 2p16-p21, between the genetic markers D2S119 and D2S288 [3].

Anatomical context of SIX3

  • SIX3 expression is normally confined specifically to the developing eye and fetal forebrain, although the expression of NR4A3 is largely ubiquitous [2].
  • By isolating specific subregions and layers of the thalamus, we identified a set of transcription factors, including Zic2, Islet1, and Six3, the unique distribution profiles of which differentiated the lateral geniculate nucleus (LGN) from the associated perigeniculate nucleus [9].
  • In both cell lines Six3 repressed the CRYGF promoter to 10% of its basal activity [10].
  • Six3 confers the ability to express Bf1, a gene essential for the telencephalon and eye development, and Nkx2.1, which is required for development of the hypothalamus [11].

Associations of SIX3 with chemical compounds

  • Using glutathione S-transferase fusion protein pull-down assays and transient cotransfections of Neuro-2a cells with expression and reporter vectors, we found that one mutation, c.676C>G (p.L226V), does not alter the properties of SIX3 toward NOR1 [1].

Physical interactions of SIX3

  • The third mutation, c.770G>C (p.R257P), results in a mutant SIX3 protein that no longer interacts with NOR1 in vivo [1].
  • In addition, geminin directly interacts with Six3 and Hox homeodomain proteins during embryogenesis and inhibits their functions [12].

Regulatory relationships of SIX3

  • In this study, we investigated the functional consequences of these SIX3 mutations with respect to the ability of the protein to interact with and stimulate the transcriptional activity of the nuclear receptor NOR1 (NR4A3) [1].

Other interactions of SIX3

  • Six3 and Six6 activity is modulated by members of the groucho family [6].
  • They include Sonic hedgehog (SHH), ZIC2, and SIX3 [13].
  • Among these patients, a deletion in the homeodomain of SIX3 and several polymorphisms in SIX3 and TGIF were identified [14].
  • In the jellyfish Cladonema radiatum, a species with well-developed lens eyes in the tentacle bulbs, Six1/2-Cr and Six3/6-Cr, are expressed in the eye cup [15].
  • During eye regeneration, expression of Six1/2-Cr and Six3/6-Cr is upregulated, but not of Six4/5-Cr [15].

Analytical, diagnostic and therapeutic context of SIX3

  • In this paper, we report extensive real-time quantitative PCR analyses of SIX3 and SIX6 expression in many different tissues of the adult human body, including ocular tissues, and a comparison of expression data with that of many other genes to identify similarity in expression [16].


  1. Functional characterization of SIX3 homeodomain mutations in holoprosencephaly: interaction with the nuclear receptor NR4A3/NOR1. Laflamme, C., Filion, C., Labelle, Y. Hum. Mutat. (2004) [Pubmed]
  2. Coexpression of NOR1 and SIX3 proteins in extraskeletal myxoid chondrosarcomas without detectable NR4A3 fusion genes. Hisaoka, M., Okamoto, S., Yokoyama, K., Hashimoto, H. Cancer Genet. Cytogenet. (2004) [Pubmed]
  3. Genomic cloning, structure, expression pattern, and chromosomal location of the human SIX3 gene. Granadino, B., Gallardo, M.E., López-Ríos, J., Sanz, R., Ramos, C., Ayuso, C., Bovolenta, P., Rodríguez de Córdoba, S. Genomics (1999) [Pubmed]
  4. Novel dominant-negative mutation within the six domain of the conserved eye specification gene sine oculis inhibits eye development in Drosophila. Roederer, K., Cozy, L., Anderson, J., Kumar, J.P. Dev. Dyn. (2005) [Pubmed]
  5. Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly. Wallis, D.E., Roessler, E., Hehr, U., Nanni, L., Wiltshire, T., Richieri-Costa, A., Gillessen-Kaesbach, G., Zackai, E.H., Rommens, J., Muenke, M. Nat. Genet. (1999) [Pubmed]
  6. Six3 and Six6 activity is modulated by members of the groucho family. López-Ríos, J., Tessmar, K., Loosli, F., Wittbrodt, J., Bovolenta, P. Development (2003) [Pubmed]
  7. Wnt signaling is required at distinct stages of development for the induction of the posterior forebrain. Braun, M.M., Etheridge, A., Bernard, A., Robertson, C.P., Roelink, H. Development (2003) [Pubmed]
  8. Regulation of the human SIX3 gene promoter. Lengler, J., Graw, J. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  9. Molecular organization of the ferret visual thalamus. Kawasaki, H., Crowley, J.C., Livesey, F.J., Katz, L.C. J. Neurosci. (2004) [Pubmed]
  10. Antagonistic action of Six3 and Prox1 at the gamma-crystallin promoter. Lengler, J., Krausz, E., Tomarev, S., Prescott, A., Quinlan, R.A., Graw, J. Nucleic Acids Res. (2001) [Pubmed]
  11. Early subdivisions in the neural plate define distinct competence for inductive signals. Kobayashi, D., Kobayashi, M., Matsumoto, K., Ogura, T., Nakafuku, M., Shimamura, K. Development (2002) [Pubmed]
  12. The regulation of embryonic patterning and DNA replication by geminin. Pitulescu, M., Kessel, M., Luo, L. Cell. Mol. Life Sci. (2005) [Pubmed]
  13. Molecular mechanisms of holoprosencephaly. Wallis, D.E., Muenke, M. Mol. Genet. Metab. (1999) [Pubmed]
  14. Holoprosencephaly: molecular study of a California population. Nanni, L., Croen, L.A., Lammer, E.J., Muenke, M. Am. J. Med. Genet. (2000) [Pubmed]
  15. The Sine oculis/Six class family of homeobox genes in jellyfish with and without eyes: development and eye regeneration. Stierwald, M., Yanze, N., Bamert, R.P., Kammermeier, L., Schmid, V. Dev. Biol. (2004) [Pubmed]
  16. Expression analysis of SIX3 and SIX6 in human tissues reveals differences in expression and a novel correlation between the expression of SIX3 and the genes encoding isocitrate dehyhrogenase and cadherin 18. Aijaz, S., Allen, J., Tregidgo, R., van Heyningen, V., Hanson, I., Clark, B.J. Genomics (2005) [Pubmed]
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