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Homeobox protein SIX3 is a protein that in humans is encoded by the SIX3 gene.[1][2][3]


The SIX homeobox 3 (SIX3) gene is crucial in embryonic development by providing necessary instructions for the formation of the forebrain and eye development. SIX3 is a transcription factor that binds to specific DNA sequences, controlling whether the gene is active or inactive. Activity of the SIX3 gene represses Wnt1 gene activity which ensures development of the forebrain and establishes the proper anterior posterior identity in the mammalian brain. By blocking Wnt1 activity, SIX3 is able to prevent abnormal expansion of the posterior portion of the brain into the anterior brain area.

During retinal development, SIX3 has been proven to hold a key responsibility in the activation of Pax6, the master regulator of eye development. Furthermore, SIX3 assumes its activity in the PLE (presumptive lens ectoderm), the region in which the lens is expected to develop. If its presence is removed from this region, the lens fails to thicken and construct itself to its proper morphological state. Also, SIX3 plays a strategic role in the activation of SOX2.

SIX3 has also been proven to play a role in repression of selected members of the Wnt family. In retinal development, SIX3 is responsible for the repression of Wnt8b. Also, in forebrain development, SIX3 is responsible for the repression of Wnt1 and activation of SHH, Sonic Hedgehog gene.

Clinical significance

Mutations in SIX3 are the cause of a severe brain malformation, called holoprosencephaly type 2 (HPE2). In HPE2, the brain fails to separate into two hemispheres during early embryonic development, leading to eye and brain malformations, which result in serious facial abnormalities.[2]

A mutant zebrafish knockout model has been developed, in which the anterior part of the head was missing due to the atypical increase of Wnt1 activity. When injected with SIX3, these zebrafish embryos were able to successfully develop a normal forebrain.[4][5] When SIX3 was turned off in mice, resulting in a lack of retina formation due to excessive expression of Wnt8b in the region where the forebrain normally develops.[6] Both of these studies demonstrate the importance of SIX3 activity in brain and eye development.


SIX3 has been shown to interact with TLE1[7] and Neuron-derived orphan receptor 1.[8][9]


  1. Granadino B, Gallardo ME, López-Ríos J, Sanz R, Ramos C, Ayuso C, Bovolenta P, Rodríguez de Córdoba S (Jan 1999). "Genomic cloning, structure, expression pattern, and chromosomal location of the human SIX3 gene". Genomics. 55 (1): 100–5. doi:10.1006/geno.1998.5611. PMID 9889003.
  2. 2.0 2.1 Wallis DE, Roessler E, Hehr U, Nanni L, Wiltshire T, Richieri-Costa A, Gillessen-Kaesbach G, Zackai EH, Rommens J, Muenke M (Jun 1999). "Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly". Nature Genetics. 22 (2): 196–8. doi:10.1038/9718. PMID 10369266.
  3. "Entrez Gene: SIX3 sine oculis homeobox homolog 3 (Drosophila)".
  4. Lagutin OV, Zhu CC, Kobayashi D, Topczewski J, Shimamura K, Puelles L, Russell HR, McKinnon PJ, Solnica-Krezel L, Oliver G (Feb 2003). "Six3 repression of Wnt signaling in the anterior neuroectoderm is essential for vertebrate forebrain development". Genes & Development. 17 (3): 368–79. doi:10.1101/gad.1059403. PMC 195989. PMID 12569128.
  5. Lavado A, Lagutin OV, Oliver G (Feb 2008). "Six3 inactivation causes progressive caudalization and aberrant patterning of the mammalian diencephalon". Development. 135 (3): 441–50. doi:10.1242/dev.010082. PMID 18094027.
  6. Liu W, Lagutin O, Swindell E, Jamrich M, Oliver G (Oct 2010). "Neuroretina specification in mouse embryos requires Six3-mediated suppression of Wnt8b in the anterior neural plate". The Journal of Clinical Investigation. 120 (10): 3568–77. doi:10.1172/JCI43219. PMC 2947236. PMID 20890044.
  7. López-Ríos J, Tessmar K, Loosli F, Wittbrodt J, Bovolenta P (Jan 2003). "Six3 and Six6 activity is modulated by members of the groucho family". Development. 130 (1): 185–95. doi:10.1242/dev.00185. PMID 12441302.
  8. Laflamme C, Filion C, Bridge JA, Ladanyi M, Goldring MB, Labelle Y (Jan 2003). "The homeotic protein Six3 is a coactivator of the nuclear receptor NOR-1 and a corepressor of the fusion protein EWS/NOR-1 in human extraskeletal myxoid chondrosarcomas". Cancer Research. 63 (2): 449–54. PMID 12543801.
  9. Ohkura N, Ohkubo T, Maruyama K, Tsukada T, Yamaguchi K (2001). "The orphan nuclear receptor NOR-1 interacts with the homeobox containing protein Six3". Developmental Neuroscience. 23 (1): 17–24. doi:10.1159/000048692. PMID 11173923.

Further reading

External links