{"results":[{"entryType":"UniProtKB reviewed (Swiss-Prot)","primaryAccession":"O95343","secondaryAccessions":["D6W5A5","Q53T42"],"uniProtkbId":"SIX3_HUMAN","entryAudit":{"firstPublicDate":"1999-07-15","lastAnnotationUpdateDate":"2026-09-02","lastSequenceUpdateDate":"1999-05-01","entryVersion":195,"sequenceVersion":1},"annotationScore":5.0,"organism":{"scientificName":"Homo sapiens","commonName":"Human","taxonId":9606,"lineage":["Eukaryota","Metazoa","Chordata","Craniata","Vertebrata","Euteleostomi","Mammalia","Eutheria","Euarchontoglires","Primates","Haplorrhini","Catarrhini","Hominidae","Homo"]},"proteinExistence":"1: Evidence at protein level","proteinDescription":{"recommendedName":{"fullName":{"value":"Homeobox protein SIX3"}},"alternativeNames":[{"fullName":{"value":"Sine oculis homeobox homolog 3"}}]},"genes":[{"geneName":{"value":"SIX3"}}],"comments":[{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q62233"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"18791198"}],"value":"Transcriptional regulator which can act as both a transcriptional repressor and activator by binding a ATTA homeodomain core recognition sequence on these target genes. During forebrain development represses WNT1 expression allowing zona limitans intrathalamica formation and thereby ensuring proper anterio-posterior patterning of the diencephalon and formation of the rostral diencephalon. Acts as a direct upstream activator of SHH expression in the rostral diencephalon ventral midline and that in turn SHH maintains its expression. In addition, Six3 activity is required for the formation of the telencephalon. During postnatal stages of brain development is necessary for ependymal cell maturation by promoting the maturation of radial glia into ependymal cells through regulation of neuroblast proliferation and migration. Acts on the proliferation and differentiation of neural progenitor cells through activating transcription of CCND1 and CCND2. During early lens formation plays a role in lens induction and specification by activating directly PAX6 in the presumptive lens ectoderm. In turn PAX6 activates SIX3 resulting in activation of PDGFRA and CCND1 promoting cell proliferation. Also is required for the neuroretina development by directly suppressing WNT8B expression in the anterior neural plate territory. Its action during retina development and lens morphogenesis is TLE5 and TLE4-dependent manner. Furthermore, during eye development regulates several genes expression. Before and during early lens development represses the CRYGF promoter by binding a SIX repressor element. Directly activates RHO transcription, or cooperates with CRX or NRL. Six3 also functions in the formation of the proximodistal axis of the optic cup, and promotes the formation of optic vesicles-like structures. During pituitary development, acts in parallel or alternatively with HESX1 to control cell proliferation through Wnt/beta-catenin pathway (By similarity). Plays a role in eye development by suppressing WNT1 expression and in dorsal-ventral patterning by repressing BMP signaling pathway"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q62233"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12441302"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12543801"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"14973488"}],"value":"Interacts with EYA4; translocates EYA4 from the cytoplasm to the nucleus and promotes activation of their target genes (By similarity). Interacts with MTA1 and HDAC2; represses its own transcription (By similarity). Interacts with MTA1; facilitates the binding of SIX3 to the core DNA motif of SIX3 promoter (By similarity). Interacts with EYA1; promotes EYA1 translocation to the nucleus (By similarity). Interacts with TLE1 and TLE5 (via Q domain); can act in combination with either TLE1 and/or TLE5 leading to transcriptional repression or activation, respectively. Interacts (via homeobox) with NR4A3; differentially regulates the transcriptional activities NR4A3. Interacts with GMNN. Interacts with TLE4"}],"commentType":"SUBUNIT"},{"commentType":"INTERACTION","interactions":[{"interactantOne":{"uniProtKBAccession":"O95343","intActId":"EBI-13644574"},"interactantTwo":{"uniProtKBAccession":"Q92570","geneName":"NR4A3","intActId":"EBI-13644623"},"numberOfExperiments":3,"organismDiffer":false}]},{"commentType":"SUBCELLULAR LOCATION","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q62233"},{"evidenceCode":"ECO:0000255","source":"PROSITE-ProRule","id":"PRU00108"}],"value":"Nucleus","id":"SL-0191"}}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"18775421"}],"value":"Expression is detected in Rathke's pouch and overlying ventral diencephalon at carnegie stage 17 and in the anterior and posterior lobes of the pituitary at carnegie stage 20. At fetal stage, expression is observed in the anterior pituitary, and the ventricular zones of the hypothalamus and telencephalic vesicles"}],"commentType":"DEVELOPMENTAL STAGE"},{"commentType":"DISEASE","disease":{"diseaseId":"Holoprosencephaly 2","diseaseAccession":"DI-00566","acronym":"HPE2","description":"A form of holoprosencephaly, a structural anomaly of the brain in which the developing forebrain fails to correctly separate into right and left hemispheres. It is a genetically and clinically heterogeneous disorder with a wide spectrum of severity, ranging from alobar holoprosencephaly with severe facial abnormalities, such as cyclopia and proboscis, to mild forms that include lobar or microform holoprosencephaly, without cerebral malformations and with mild craniofacial defects. HPE2 inheritance is autosomal dominant.","diseaseCrossReference":{"database":"MIM","id":"157170"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10369266"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"15221788"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"15523651"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"17001667"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"18791198"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"20531442"}]},"note":{"texts":[{"value":"The disease is caused by variants affecting the gene represented in this entry"}]}},{"commentType":"DISEASE","disease":{"diseaseId":"Schizencephaly","diseaseAccession":"DI-02284","acronym":"SCHZC","description":"Extremely rare human congenital disorder characterized by a full-thickness cleft within the cerebral hemispheres. These clefts are lined with gray matter and most commonly involve the parasylvian regions. 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