SIX3

Homeobox protein SIX3 is a protein that in humans is encoded by the SIX3 gene.[5][6][7]

SIX3
Identifiers
AliasesSIX3, HPE2, SIX homeobox 3
External IDsOMIM: 603714 MGI: 102764 HomoloGene: 3947 GeneCards: SIX3
Gene location (Human)
Chr.Chromosome 2 (human)[1]
Band2p21Start44,941,702 bp[1]
End44,946,071 bp[1]
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
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 MbChr 17: 85.61 – 85.63 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[6]

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.[8][9] 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.[10] Both of these studies demonstrate the importance of SIX3 activity in brain and eye development.

Interactions

SIX3 has been shown to interact with TLE1[11] and Neuron-derived orphan receptor 1.[12][13]

References
  1. GRCh38: Ensembl release 89: ENSG00000138083 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000038805 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 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.
  6. 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.
  7. "Entrez Gene: SIX3 sine oculis homeobox homolog 3 (Drosophila)".
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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
  • 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.
  • 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. 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. doi:10.1038/nature02292. PMID 14973488.
  • 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.
  • 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.
  • 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.
  • 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. doi:10.1073/pnas.0705878104. PMC 1941821. PMID 17666527.
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