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Gene Review

SIX4  -  SIX homeobox 4

Homo sapiens

Synonyms: AREC3, Homeobox protein SIX4, Sine oculis homeobox homolog 4
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High impact information on SIX4

  • The mammalian SIX5/SIX4 gene pair is likely to be involved in the development of mesodermal structures [1].
  • Structure, function and expression of a murine homeobox protein AREC3, a homologue of Drosophila sine oculis gene product, and implication in development [2].
  • This common primordium is defined by the expression of transcription factors of the Six1/2, Six4/5, and Eya families, which later continue to be expressed in all placodes and appear to promote generic placodal properties such as proliferation, the capacity for morphogenetic movements, and neuronal differentiation [3].
  • During eye regeneration, expression of Six1/2-Cr and Six3/6-Cr is upregulated, but not of Six4/5-Cr [4].
  • Six4/5-Cr is mainly expressed in the manubrium, the feeding, and sex organ [4].

Biological context of SIX4

  • Chromosomal mapping of SIX6 revealed that it is closely linked to SIX1 and SIX4 in human chromosome 14q22.3-q23, which provides clues about the origin and evolution of the vertebrate SIX family [5].
  • Human SIX4 was mapped to chromosome 14q23 [6].
  • The Six1/Six4-deficient mice exhibited more severe kidney phenotypes than the Six1-deficient mice; kidney and ureter agenesis was observed in all the neonates examined [7].
  • Loss of both Six1 and Six4 in mice caused severe defects in the trigeminal ganglia, wherein massive apoptosis accompanied by activation of caspase-3 was observed at early but not late stages of gangliogenesis [8].

Anatomical context of SIX4

  • These results highlight the fact that Six1 and Six4 have collaborative functions in the metanephros but not in the mesonephros [7].
  • Six1 and Six4 are the mammalian homologs of Drosophila sine oculis, and they are coexpressed in the nephrogenic mesenchyme [7].
  • Six1 and Six4 promote survival of sensory neurons during early trigeminal gangliogenesis [8].
  • In the present study, we investigated the role of Six1 and Six4 in the development of trigeminal ganglia [8].

Analytical, diagnostic and therapeutic context of SIX4

  • Western blot analysis indicated that the 115 kDa form of AREC3 protein is increased in the cytoplasmic extract, and the 67kDa form is increased both in nuclear and cytoplasmic extracts of C2C12 cells during muscle differentiation [2].


  1. Drosophila homolog of the myotonic dystrophy-associated gene, SIX5, is required for muscle and gonad development. Kirby, R.J., Hamilton, G.M., Finnegan, D.J., Johnson, K.J., Jarman, A.P. Curr. Biol. (2001) [Pubmed]
  2. Structure, function and expression of a murine homeobox protein AREC3, a homologue of Drosophila sine oculis gene product, and implication in development. Kawakami, K., Ohto, H., Ikeda, K., Roeder, R.G. Nucleic Acids Res. (1996) [Pubmed]
  3. Induction and specification of cranial placodes. Schlosser, G. Dev. Biol. (2006) [Pubmed]
  4. 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]
  5. Genomic cloning and characterization of the human homeobox gene SIX6 reveals a cluster of SIX genes in chromosome 14 and associates SIX6 hemizygosity with bilateral anophthalmia and pituitary anomalies. Gallardo, M.E., Lopez-Rios, J., Fernaud-Espinosa, I., Granadino, B., Sanz, R., Ramos, C., Ayuso, C., Seller, M.J., Brunner, H.G., Bovolenta, P., Rodríguez de Córdoba, S. Genomics (1999) [Pubmed]
  6. Structure and chromosome mapping of the human SIX4 and murine Six4 genes. Ozaki, H., Yamada, K., Kobayashi, M., Asakawa, S., Minoshima, S., Shimizu, N., Kajitani, M., Kawakami, K. Cytogenet. Cell Genet. (1999) [Pubmed]
  7. Six1 and Six4 are essential for Gdnf expression in the metanephric mesenchyme and ureteric bud formation, while Six1 deficiency alone causes mesonephric-tubule defects. Kobayashi, H., Kawakami, K., Asashima, M., Nishinakamura, R. Mech. Dev. (2007) [Pubmed]
  8. Six1 and Six4 promote survival of sensory neurons during early trigeminal gangliogenesis. Konishi, Y., Ikeda, K., Iwakura, Y., Kawakami, K. Brain Res. (2006) [Pubmed]
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