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Gene Review

Six2  -  sine oculis-related homeobox 2

Mus musculus

Synonyms: Homeobox protein SIX2, Sine oculis homeobox homolog 2
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High impact information on Six2

  • Six2 expression, however, is absent, as is expression of the inducing growth factor, Gdnf [1].
  • Hoxa2 downregulates Six2 in the neural crest-derived mesenchyme [2].
  • We have identified two murine homeobox-containing genes, Six 1 and Six 2, which are expressed in a complementary fashion during the development of limb tendons [3].
  • Six 1 and Six 2 also are expressed in skeletal and smooth muscle, respectively [3].
  • In order to identify factors which activate expression of Six2, particularly in the metanephric mesenchyme during early kidney development we have cloned and characterized a 930 bp fragment of the murine Six2 promoter [4].

Biological context of Six2

  • By using a transgenic approach to overexpress Six2 in the embryonic area controlled by Hoxa2, we observed a phenotype that is reminiscent of the Hoxa2 mutant phenotype [2].
  • The architecture of the binding sites in the Six2 promoter, but not the binding sequence itself, is very similar to the one in the Gdnf promoter [4].
  • Furthermore, we have characterized the Six2 protein and show that Six2 possesses a transcriptional activation domain in the C-terminus and nuclear localization determinants in the Six domain [4].
  • Transgenic mice harboring a construct in which the LacZ gene is driven by the Six2 promoter fragment revealed LacZ expression at multiple sites which overlap with endogenous Six2 expression [4].

Anatomical context of Six2

  • Two Six2 subfamily genes (Six1, Six2) showed very similar expression patterns in cranial ganglia, otic placodes and the eyes [5].
  • Non-neural expression of Six1 and Six2 was observed with mesodermal head mesenchyme, somites and their derivatives, the muscle anlagen of the embryonic trunk [5].
  • Production of Six2 was detected at E8.5 mainly in the mesenchyme, while Six4 was present in nuclei of neuronal cells in the peripheral region of the mantle layer of developing brain and spinal cord and in various ganglia at E10.5 and E11 [6].

Physical interactions of Six2

  • We have identified two Six2 binding sites in the Gdnf promoter that show similarity to the consensus DNA binding sequences of other homeobox proteins and harbor short palindromic sequences [4].

Regulatory relationships of Six2

  • The transcription factor Six2 activates expression of the Gdnf gene as well as its own promoter [4].

Other interactions of Six2

  • These results strongly suggest that Six2 is a direct target of Hoxa2 [2].
  • The distribution of Six2 and Six4 was examined by immunostaining in the developing mouse embryo [6].
  • We show here that a member of the Six family of homeobox containing transcription factors, namely Six2 activates Gdnf expression [4].


  1. Hox11 paralogous genes are essential for metanephric kidney induction. Wellik, D.M., Hawkes, P.J., Capecchi, M.R. Genes Dev. (2002) [Pubmed]
  2. Hoxa2 downregulates Six2 in the neural crest-derived mesenchyme. Kutejova, E., Engist, B., Mallo, M., Kanzler, B., Bobola, N. Development (2005) [Pubmed]
  3. Homeobox genes and connective tissue patterning. Oliver, G., Wehr, R., Jenkins, N.A., Copeland, N.G., Cheyette, B.N., Hartenstein, V., Zipursky, S.L., Gruss, P. Development (1995) [Pubmed]
  4. The transcription factor Six2 activates expression of the Gdnf gene as well as its own promoter. Brodbeck, S., Besenbeck, B., Englert, C. Mech. Dev. (2004) [Pubmed]
  5. Molecular cloning and embryonic expression of Xenopus Six homeobox genes. Ghanbari, H., Seo, H.C., Fjose, A., Brändli, A.W. Mech. Dev. (2001) [Pubmed]
  6. Tissue and developmental distribution of Six family gene products. Ohto, H., Takizawa, T., Saito, T., Kobayashi, M., Ikeda, K., Kawakami, K. Int. J. Dev. Biol. (1998) [Pubmed]
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