SIX3

SIX3
Identifiers
Aliases	SIX3, HPE2, SIX homeobox 3
External IDs	OMIM: 603714; MGI: 102764; HomoloGene: 3947; GeneCards: SIX3; OMA:SIX3 - orthologs
Gene location (Human) Chr. Chromosome 2 (human) Band 2p21 Start 44,941,702 bp End 44,946,071 bp
Gene location (Mouse) Chr. Chromosome 17 (mouse) Band 17 E4|17 55.42 cM Start 85,921,036 bp End 85,936,730 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in retinal pigment epithelium nasal epithelium nucleus accumbens mucosa of paranasal sinus optic nerve caudate nucleus putamen olfactory zone of nasal mucosa anterior pituitary buccal mucosa cell Top expressed in optic vesicle epithelium of lens pretectal area subthalamus neural layer of retina zona incerta suprachiasmatic nucleus optic recess thalamic reticular nucleus optic stalk More reference expression data BioGPS More reference expression data
Gene ontology Molecular function RNA polymerase II cis-regulatory region sequence-specific DNA binding DNA binding sequence-specific DNA binding DNA-binding transcription factor activity transcription coactivator activity histone deacetylase binding DNA-binding transcription activator activity, RNA polymerase II-specific protein binding transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding transcription corepressor binding signaling receptor binding DNA-binding transcription factor activity, RNA polymerase II-specific transcription cis-regulatory region binding Cellular component nucleus transcription regulator complex Biological process eye development forebrain anterior/posterior pattern specification pituitary gland development regulation of transcription, DNA-templated negative regulation of neuron differentiation proximal/distal axis specification lens fiber cell apoptotic process protein import into nucleus neuroblast differentiation forebrain dorsal/ventral pattern formation optic vesicle morphogenesis negative regulation of Wnt signaling pathway apoptotic process involved in development transcription by RNA polymerase II regulation of neural precursor cell proliferation transcription, DNA-templated regulation of neural retina development multicellular organism development telencephalon regionalization diencephalon development telencephalon development brain development lens development in camera-type eye lens fiber cell differentiation regulation of cell population proliferation regulation of neuroblast proliferation lens induction in camera-type eye epithelial cell maturation neuroblast migration circadian behavior camera-type eye development negative regulation of transcription, DNA-templated cell proliferation in forebrain positive regulation of transcription by RNA polymerase II visual perception regulation of cell cycle phase transition anatomical structure development Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 6496 20473 Ensembl ENSG00000138083 ENSMUSG00000038805 UniProt O95343 Q62233 RefSeq (mRNA) NM_005413 NM_011381 RefSeq (protein) NP_005404 NP_035511 Location (UCSC) Chr 2: 44.94 – 44.95 Mb Chr 17: 85.92 – 85.94 Mb PubMed search
Wikidata
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Homeobox protein SIX3 is a protein that in humans is encoded by the SIX3 gene.

Function

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.

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. When SIX3 was turned off in mice, it resulted 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.

Interactions

SIX3 has been shown to interact with TLE1 and Neuron-derived orphan receptor 1.

Further reading

• 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. PMID 1887845.
• 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. PMID 10415461.
• Ohto H, Kamada S, Tago K, Tominaga SI, Ozaki H, Sato S, Kawakami K (Oct 1999). "Cooperation of six and eya in activation of their target genes through nuclear translocation of Eya". Molecular and Cellular Biology. 19 (10): 6815–24. doi:10.1128/mcb.19.10.6815. PMC 84678. PMID 10490620.
• 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. PMID 11069920.
• 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. S2CID 84167063.
• 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. PMID 11554737.
• 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. PMID 12050133.
• 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.
• 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.
• Del Bene F, Tessmar-Raible K, Wittbrodt J (Feb 2004). "Direct interaction of geminin and Six3 in eye development". Nature. 427 (6976): 745–9. Bibcode:2004Natur.427..745B. doi:10.1038/nature02292. PMID 14973488. S2CID 4410030.
• 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. PMID 15221788. S2CID 34076824.
• 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. PMID 15523651. S2CID 42925900.
• Pasquier L, Dubourg C, Gonzales M, Lazaro L, David V, Odent S, Encha-Razavi F (Jan 2005). "First occurrence of aprosencephaly/atelencephaly and holoprosencephaly in a family with a SIX3 gene mutation and phenotype/genotype correlation in our series of SIX3 mutations". Journal of Medical Genetics. 42 (1): e4. doi:10.1136/jmg.2004.023416. PMC 1735902. PMID 15635066.
• 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. PMID 16323008. S2CID 24211129.
• Manavathi B, Peng S, Rayala SK, Talukder AH, Wang MH, Wang RA, Balasenthil S, Agarwal N, Frishman LJ, Kumar R (Aug 2007). "Repression of Six3 by a corepressor regulates rhodopsin expression". Proceedings of the National Academy of Sciences of the United States of America. 104 (32): 13128–33. Bibcode:2007PNAS..10413128M. doi:10.1073/pnas.0705878104. PMC 1941821. PMID 17666527.

External links

• GeneReviews/NCBI/NIH/UW entry on Anophthalmia / Microphthalmia Overview