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.
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.
A mutant zebrafishknockout 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. 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. Both of these studies demonstrate the importance of SIX3 activity in brain and eye development.
^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. PMID9889003.
^ abWallis 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. PMID10369266.
^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. PMID18094027.
^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. PMID12441302.
^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. PMID12543801.
^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. PMID11173923.
Hecht BK, Hecht F, Münke M (Jul 1991). "Forebrain cleavage gene causing holoprosencephaly: deletion mapping to chromosome band 2p21". American Journal of Medical Genetics. 40 (1): 130. doi:10.1002/ajmg.1320400131. PMID1887845.
Leppert GS, Yang JM, Sundin OH (Mar 1999). "Sequence and location of SIX3, a homeobox gene expressed in the human eye". Ophthalmic Genetics. 20 (1): 7–21. doi:10.1076/opge.184.108.40.2068. PMID10415461.
Mikkola I, Bruun JA, Holm T, Johansen T (Feb 2001). "Superactivation of Pax6-mediated transactivation from paired domain-binding sites by dna-independent recruitment of different homeodomain proteins". The Journal of Biological Chemistry. 276 (6): 4109–18. doi:10.1074/jbc.M008882200. PMID11069920.
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. PMID11173923.
Lengler J, Graw J (Sep 2001). "Regulation of the human SIX3 gene promoter". Biochemical and Biophysical Research Communications. 287 (2): 372–6. doi:10.1006/bbrc.2001.5605. PMID11554737.
Zhu CC, Dyer MA, Uchikawa M, Kondoh H, Lagutin OV, Oliver G (Jun 2002). "Six3-mediated auto repression and eye development requires its interaction with members of the Groucho-related family of co-repressors". Development. 129 (12): 2835–49. PMID12050133.
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. PMID12441302.
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. PMID12543801.
Del Bene F, Tessmar-Raible K, Wittbrodt J (Feb 2004). "Direct interaction of geminin and Six3 in eye development". Nature. 427 (6976): 745–9. doi:10.1038/nature02292. PMID14973488.
Dubourg C, Lazaro L, Pasquier L, Bendavid C, Blayau M, Le Duff F, Durou MR, Odent S, David V (Jul 2004). "Molecular screening of SHH, ZIC2, SIX3, and TGIF genes in patients with features of holoprosencephaly spectrum: Mutation review and genotype-phenotype correlations". Human Mutation. 24 (1): 43–51. doi:10.1002/humu.20056. PMID15221788.
Laflamme C, Filion C, Labelle Y (Dec 2004). "Functional characterization of SIX3 homeodomain mutations in holoprosencephaly: interaction with the nuclear receptor NR4A3/NOR1". Human Mutation. 24 (6): 502–8. doi:10.1002/humu.20102. PMID15523651.
Bendavid C, Dubourg C, Gicquel I, Pasquier L, Saugier-Veber P, Durou MR, Jaillard S, Frébourg T, Haddad BR, Henry C, Odent S, David V (Mar 2006). "Molecular evaluation of foetuses with holoprosencephaly shows high incidence of microdeletions in the HPE genes". Human Genetics. 119 (1-2): 1–8. doi:10.1007/s00439-005-0097-6. PMID16323008.