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 significanceedit
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 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.[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.
^ abcGRCh38: Ensembl release 89: ENSG00000138083 - Ensembl, May 2017
^ abcGRCm38: Ensembl release 89: ENSMUSG00000038805 - Ensembl, May 2017
^"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. PMID 9889003.
^ 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. PMID 10369266. S2CID 8319986.
^"Entrez Gene: SIX3 sine oculis homeobox homolog 3 (Drosophila)".
^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. PMC195989. PMID 12569128.
^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.
^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. PMC2947236. PMID 20890044.
^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.
^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.
Further readingedit
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. PMC84678. 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. PMC1735902. 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. PMC1941821. PMID 17666527.
External linksedit
GeneReviews/NCBI/NIH/UW entry on Anophthalmia / Microphthalmia Overview
December 18, 2023
six3, homeobox, protein, protein, that, humans, encoded, gene, identifiersaliases, hpe2, homeobox, 3external, idsomim, 603714, 102764, homologene, 3947, genecards, gene, location, human, chromosome, human, band2p21start44, end44, gene, location, mouse, chromos. Homeobox protein SIX3 is a protein that in humans is encoded by the SIX3 gene 5 6 7 SIX3IdentifiersAliasesSIX3 HPE2 SIX homeobox 3External IDsOMIM 603714 MGI 102764 HomoloGene 3947 GeneCards SIX3Gene location Human Chr Chromosome 2 human 1 Band2p21Start44 941 702 bp 1 End44 946 071 bp 1 Gene location Mouse Chr Chromosome 17 mouse 2 Band17 E4 17 55 42 cMStart85 921 036 bp 2 End85 936 730 bp 2 RNA expression patternBgeeHumanMouse ortholog Top expressed inretinal pigment epitheliumnucleus accumbensoptic nervecaudate nucleusputamenanterior pituitaryexternal globus pallidushypothalamusislet of LangerhansspermTop expressed inoptic vesiclepretectal areasubthalamuszona incertasuprachiasmatic nucleusoptic recessthalamic reticular nucleusnucleus accumbensmedial habenular nucleusmedial ganglionic eminenceMore reference expression dataBioGPSMore reference expression dataGene ontologyMolecular functionRNA 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 bindingCellular componentnucleus transcription regulator complexBiological processeye 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 developmentSources Amigo QuickGOOrthologsSpeciesHumanMouseEntrez649620473EnsemblENSG00000138083ENSMUSG00000038805UniProtO95343Q62233RefSeq mRNA NM 005413NM 011381RefSeq protein NP 005404NP 035511Location UCSC Chr 2 44 94 44 95 MbChr 17 85 92 85 94 MbPubMed search 3 4 WikidataView Edit HumanView Edit Mouse Contents 1 Function 2 Clinical significance 3 Interactions 4 References 5 Further reading 6 External linksFunction editThe 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 editMutations 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 editSIX3 has been shown to interact with TLE1 11 and Neuron derived orphan receptor 1 12 13 References edit a b c GRCh38 Ensembl release 89 ENSG00000138083 Ensembl May 2017 a b c GRCm38 Ensembl release 89 ENSMUSG00000038805 Ensembl May 2017 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 Lopez Rios J Sanz R Ramos C Ayuso C Bovolenta P Rodriguez de Cordoba 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 a b 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 S2CID 8319986 Entrez Gene SIX3 sine oculis homeobox homolog 3 Drosophila 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 amp Development 17 3 368 79 doi 10 1101 gad 1059403 PMC 195989 PMID 12569128 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 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 Lopez Rios 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 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 Further reading editHecht BK Hecht F Munke 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 Lopez Rios 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 Frebourg 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 editGeneReviews NCBI NIH UW entry on Anophthalmia Microphthalmia Overview Retrieved from https en wikipedia org w index php title SIX3 amp oldid 1170968726, wikipedia, wiki, book, books, library,
