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Homeobox protein SIX3



Mus musculus (Mouse)
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli


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 (PubMed:18094027). Acts as a direct upstream activator of SHH expression in the rostral diencephalon ventral midline and that in turn SHH maintains its expression (PubMed:18775421). 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 (PubMed:22071110). Acts on the proliferation and differentiation of neural progenitor cells through activating transcription of CCND1 AND CCND2 (PubMed:17576749). During early lens formation plays a role in lens induction and specification by activating directly PAX6 in the presumptive lens ectoderm (PubMed:17066077). In turn PAX6 activates SIX3 resulting in activation of PDGFRA and CCND1 promoting cell proliferation (PubMed:12072567). Also is required for the neuroretina development by directly suppressing WNT8B expression in the anterior neural plate territory (PubMed:20890044). Its action during retina development and lens morphogenesis is AES 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 (PubMed:11139622). Directly activates RHO transcription, or cooperates with CRX or NRL (PubMed:17666527). Six3 functions also in the formation of the proximodistal axis of the optic cup (PubMed:12163408), and promotes the formation of optic vesicles-like structures (PubMed:11458394). During pituitary development, acts in parallel or alternatively with HESX1 to control cell proliferation through Wnt/beta-catenin pathway (PubMed:18694563). Plays a role in eye development by suppressing WNT1 expression and in dorsal-ventral patterning by repressing BMP signaling pathway (By similarity).By similarity15 Publications


Feature keyPosition(s)DescriptionActionsGraphical viewLength
DNA bindingi207 – 266HomeoboxPROSITE-ProRule annotationAdd BLAST60

GO - Molecular functioni

  • DNA binding Source: MGI
  • histone deacetylase binding Source: UniProtKB
  • receptor binding Source: Ensembl
  • RNA polymerase II distal enhancer sequence-specific DNA binding Source: NTNU_SB
  • sequence-specific DNA binding Source: MGI
  • transcriptional activator activity, RNA polymerase II distal enhancer sequence-specific binding Source: NTNU_SB
  • transcription coactivator activity Source: UniProtKB
  • transcription corepressor binding Source: UniProtKB
  • transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding Source: MGI
  • transcription factor activity, sequence-specific DNA binding Source: UniProtKB

GO - Biological processi

  • apoptotic process involved in development Source: UniProtKB
  • brain development Source: MGI
  • camera-type eye development Source: MGI
  • cell proliferation in forebrain Source: UniProtKB
  • circadian behavior Source: MGI
  • diencephalon development Source: MGI
  • epithelial cell maturation Source: UniProtKB
  • eye development Source: MGI
  • forebrain anterior/posterior pattern specification Source: MGI
  • forebrain dorsal/ventral pattern formation Source: UniProtKB
  • lens development in camera-type eye Source: UniProtKB
  • lens fiber cell apoptotic process Source: UniProtKB
  • lens fiber cell differentiation Source: UniProtKB
  • lens induction in camera-type eye Source: MGI
  • negative regulation of neuron differentiation Source: UniProtKB
  • negative regulation of transcription, DNA-templated Source: UniProtKB
  • negative regulation of Wnt signaling pathway Source: MGI
  • neuroblast differentiation Source: UniProtKB
  • neuroblast migration Source: UniProtKB
  • optic vesicle morphogenesis Source: UniProtKB
  • pituitary gland development Source: UniProtKB
  • positive regulation of transcription from RNA polymerase II promoter Source: NTNU_SB
  • protein import into nucleus Source: MGI
  • protein import into nucleus, translocation Source: UniProtKB
  • proximal/distal axis specification Source: UniProtKB
  • regulation of cell cycle phase transition Source: UniProtKB
  • regulation of cell proliferation Source: UniProtKB
  • regulation of neural precursor cell proliferation Source: UniProtKB
  • regulation of neural retina development Source: UniProtKB
  • regulation of neuroblast proliferation Source: UniProtKB
  • telencephalon development Source: UniProtKB
  • telencephalon regionalization Source: UniProtKB


Molecular functionDevelopmental protein, DNA-binding, Repressor
Biological processTranscription, Transcription regulation

Names & Taxonomyi

Protein namesi
Recommended name:
Homeobox protein SIX3
Alternative name(s):
Sine oculis homeobox homolog 3
Gene namesi
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
  • UP000000589 Componenti: Chromosome 17

Organism-specific databases

MGIiMGI:102764. Six3.

Subcellular locationi

  • Nucleus PROSITE-ProRule annotation1 Publication

GO - Cellular componenti

  • nucleus Source: MGI

Keywords - Cellular componenti


Pathology & Biotechi

Disruption phenotypei

Embryos die at birth and lack most head structures anterior to the midbrain, including the eyes and nose (PubMed:12569128). Embryonic SHH and SIX3 double heterozygous mice exibit a semilobar holoprosencephaly-like phenotype and a dorsoventral patterning defects in telencephalon (PubMed:18694563). Embryonic WNT1 and SIX3 double homozygous mice lack cerebellum and colliculus and have a severely reduced midbrain (PubMed:18094027). Conditional knockout in eye exibit drastically reduced lens size, cataracts, or absence of the lens (PubMed:17066077). Embryo of SIX3 and HESX1 heterozygous mice exhibit severe growth retardation after weaning, with additional gonadal and thyroid gland defects, resulting in a lethal phenotype (PubMed:18775421).5 Publications


Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi88F → E: Loss of interaction with AES and TLE4. 1 Publication1
Mutagenesisi233 – 235Missing : Suppression of SIX3-binding to rhodopsin promoter. Impairs the ability of Six3 to stimulate RHO transcription. 1 Publication3

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000493001 – 333Homeobox protein SIX3Add BLAST333

Proteomic databases


PTM databases



Tissue specificityi

Expressed in ependymal cells during the formation of the lateral wall.1 Publication

Developmental stagei

Expressed in the developing retina (at protein level). First expressed at E6.5 of embryo development around the anterior border. At E8.5, expression is found over the anterior neural plate. At E9.5, in the diencephalic part of the ventral forebrain, optic vesicles, olfactory placodes and Rathke pouch. In later stages, present in hypothalamus, eyes and pituitary. Expression at around E7.5 to E8 is high in the anterior neural ectoderm. Weaker expression is detected in the prechordal plate. At the 5 somite stage (E8.0), expression is maintained in the anterior neural ectoderm. Around the 8 somite stage (E8.0), expression is already restricted to the ventral forebrain and eye field. At the 12 somite stage (E8.5), expression is maintained in the ventral forebrain (PubMed:18694563). At E9.5 strongly expressed throughout the prospective nasal ectoderm. At E10.5 remains expressed throughout the nasal ectoderm (PubMed:16024294). At E7.5 expression is found in the developing anterior neuroectoderm. At E9.0 expression is found in the region of the presumptive lens ectoderm and developing optic vesicle. At E9.5 expression is found in the lens placode, optic vesicles, and ventral forebrain (PubMed:11458394).3 Publications


Represses its own transcription in a TLE4-dependent manner. Induces in lens by PAX6 in a dosage-dependent manner. Activated by SOX2 during forebrain development. Inhibited by MTA1 in mammary glands.3 Publications

Gene expression databases

ExpressionAtlasiQ62233. baseline and differential.
GenevisibleiQ62233. MM.


Subunit structurei

Interacts with EYA4; translocates EYA4 from the cytoplasm to the nucleus and promotes activation of their target genes. Interacts with MTA1 and HDAC2; represses its own transcription. Interacts with MTA1; facilitates the binding of SIX3 to the core DNA motif of SIX3 promoter. Interacts with EYA1; promotes EYA1 translocation to the nucleus. Interacts with TLE1 and AES (via Q domain); can act in combination with either TLE1 and/or AES leading to transcriptional repression or activation, respectively (By similarity). Interacts (via homeobox) with NR4A3; differentially regulates the transcriptional activities NR4A3 (By similarity). Interacts with GMNN (By similarity). Interacts with TLE4.By similarity4 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • histone deacetylase binding Source: UniProtKB
  • receptor binding Source: Ensembl
  • transcription corepressor binding Source: UniProtKB

Protein-protein interaction databases

BioGridi203261. 4 interactors.
IntActiQ62233. 3 interactors.


3D structure databases


Family & Domainsi


Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni73 – 120Interaction with AES1 PublicationAdd BLAST48
Regioni233 – 235Bind to RHO promoter1 Publication3

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi33 – 70Gly-richPROSITE-ProRule annotationAdd BLAST38

Sequence similaritiesi

Belongs to the SIX/Sine oculis homeobox family.Curated

Keywords - Domaini


Phylogenomic databases

eggNOGiKOG0775. Eukaryota.

Family and domain databases

InterProiView protein in InterPro
IPR009057. Homeobox-like.
IPR001356. Homeobox_dom.
IPR031701. SIX1_SD.
IPR032949. SIX3.
PANTHERiPTHR10390:SF43. PTHR10390:SF43. 1 hit.
PfamiView protein in Pfam
PF00046. Homeobox. 1 hit.
PF16878. SIX1_SD. 1 hit.
SMARTiView protein in SMART
SM00389. HOX. 1 hit.
SUPFAMiSSF46689. SSF46689. 1 hit.
PROSITEiView protein in PROSITE
PS50071. HOMEOBOX_2. 1 hit.

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform SIX3B1 Publication (identifier: Q62233-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

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110 120 130 140 150
160 170 180 190 200
210 220 230 240 250
260 270 280 290 300
310 320 330
Mass (Da):35,593
Last modified:December 15, 1998 - v2
Isoform SIX3A1 Publication (identifier: Q62233-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     285-333: Missing.

Show »
Mass (Da):30,610

Sequence cautioni

The sequence CAA62379 differs from that shown. Reason: Frameshift at positions 117, 119 and 277.Curated
The sequence CAA62379 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti44G → GG in CAA62379 (PubMed:8575305).Curated1
Sequence conflicti283S → C in CAA62379 (PubMed:8575305).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_002291271 – 284LQHQA…GMRSL → SVAGTAARPPQAPG in isoform SIX3A. CuratedAdd BLAST14
Alternative sequenceiVSP_002292285 – 333Missing in isoform SIX3A. CuratedAdd BLAST49

Sequence databases

Select the link destinations:
Links Updated
X90871 mRNA. Translation: CAA62379.1. Sequence problems.
D83144 mRNA. Translation: BAA11822.1.
D83145 mRNA. Translation: BAA11823.1.
BC098096 mRNA. Translation: AAH98096.1.
CCDSiCCDS50203.1. [Q62233-1]
RefSeqiNP_035511.2. NM_011381.4. [Q62233-1]

Genome annotation databases

EnsembliENSMUST00000175898; ENSMUSP00000135677; ENSMUSG00000038805. [Q62233-1]
ENSMUST00000176081; ENSMUSP00000135312; ENSMUSG00000038805. [Q62233-1]
UCSCiuc008dub.2. mouse. [Q62233-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.

Entry informationi

Entry nameiSIX3_MOUSE
AccessioniPrimary (citable) accession number: Q62233
Secondary accession number(s): P70176, P70177, Q4QQQ3
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: December 15, 1998
Last modified: May 10, 2017
This is version 139 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program


Keywords - Technical termi

Complete proteome, Reference proteome


  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. SIMILARITY comments
    Index of protein domains and families