Biology:SIX3

Short description: Protein-coding gene in the species Homo sapiens

Generic protein structure example

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

• "Forebrain cleavage gene causing holoprosencephaly: deletion mapping to chromosome band 2p21". American Journal of Medical Genetics 40 (1): 130. Jul 1991. doi:10.1002/ajmg.1320400131. PMID 1887845. 
• "Sequence and location of SIX3, a homeobox gene expressed in the human eye". Ophthalmic Genetics 20 (1): 7–21. Mar 1999. doi:10.1076/opge.20.1.7.2298. PMID 10415461. 
• "Cooperation of six and eya in activation of their target genes through nuclear translocation of Eya". Molecular and Cellular Biology 19 (10): 6815–24. Oct 1999. doi:10.1128/mcb.19.10.6815. PMID 10490620. 
• "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. Feb 2001. doi:10.1074/jbc.M008882200. PMID 11069920. 
• "The orphan nuclear receptor NOR-1 interacts with the homeobox containing protein Six3". Developmental Neuroscience 23 (1): 17–24. 2001. doi:10.1159/000048692. PMID 11173923. 
• "Regulation of the human SIX3 gene promoter". Biochemical and Biophysical Research Communications 287 (2): 372–6. Sep 2001. doi:10.1006/bbrc.2001.5605. PMID 11554737. 
• "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. Jun 2002. doi:10.1242/dev.129.12.2835. PMID 12050133. 
• "Six3 and Six6 activity is modulated by members of the groucho family". Development 130 (1): 185–95. Jan 2003. doi:10.1242/dev.00185. PMID 12441302. 
• "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. Jan 2003. PMID 12543801. 
• "Direct interaction of geminin and Six3 in eye development". Nature 427 (6976): 745–9. Feb 2004. doi:10.1038/nature02292. PMID 14973488. Bibcode: 2004Natur.427..745B. 
• "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. Jul 2004. doi:10.1002/humu.20056. PMID 15221788. 
• "Functional characterization of SIX3 homeodomain mutations in holoprosencephaly: interaction with the nuclear receptor NR4A3/NOR1". Human Mutation 24 (6): 502–8. Dec 2004. doi:10.1002/humu.20102. PMID 15523651. 
• "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. Jan 2005. doi:10.1136/jmg.2004.023416. PMID 15635066. 
• "Molecular evaluation of foetuses with holoprosencephaly shows high incidence of microdeletions in the HPE genes". Human Genetics 119 (1–2): 1–8. Mar 2006. doi:10.1007/s00439-005-0097-6. PMID 16323008. 
• "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. Aug 2007. doi:10.1073/pnas.0705878104. PMID 17666527. Bibcode: 2007PNAS..10413128M. 

External links

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