The SIX homeobox 3 (SIX3) gene is crucial inembryonic development by providing necessary instructions for the formation of theforebrain andeye development. SIX3 is atranscription factor that binds to specificDNA sequences, controlling whether the gene is active or inactive. Activity of the SIX3 gene repressesWnt1 gene activity which ensures development of the forebrain and establishes the proper anterior posterior identity in themammalian 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 ofPax6, the master regulator ofeye development. Furthermore, SIX3 assumes its activity in the PLE (presumptive lensectoderm), the region in which thelens 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 ofSOX2.
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 ofWnt8b. 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, calledholoprosencephaly type 2 (HPE2). In HPE2, the brain fails to separate into twohemispheres during early embryonic development, leading to eye and brain malformations, which result in serious facial abnormalities.[6]
A mutantzebrafishknockout model has been developed, in which the anterior part of the head was missing due to the atypical increase ofWnt1 activity. When injected with SIX3, these zebrafish embryos were able to successfully develop a normal forebrain.[8][9] When SIX3 was turned off in mice, it resulted in a lack of retina formation due to excessive expression ofWnt8b in the region where the forebrain normally develops.[10] Both of these studies demonstrate the importance of SIX3 activity in brain and eye development.
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^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.S2CID8319986.
^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.S2CID1838148.
^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.S2CID84167063.
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.20.1.7.2298.PMID10415461.
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.S2CID84167063.
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.doi:10.1242/dev.129.12.2835.PMID12050133.
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.
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.S2CID34076824.
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.S2CID24211129.
