Q61321 · SIX4_MOUSE

  • Protein
    Homeobox protein SIX4
  • Gene
    Six4
  • Status
    UniProtKB reviewed (Swiss-Prot)
  • Amino acids
  • Protein existence
    Evidence at protein level
  • Annotation score
    5/5

Function

function

Transcriptional regulator which can act as both a transcriptional repressor and activator by binding a DNA sequence on these target genes and is involved in processes like cell differentiation, cell migration and cell survival. Transactivates gene expression by binding a 5'-[CAT]A[CT][CT][CTG]GA[GAT]-3' motif present in the Trex site and from a 5'-TCA[AG][AG]TTNC-3' motif present in the MEF3 site of the muscle-specific genes enhancer (PubMed:14966291).
Acts cooperatively with EYA proteins to transactivate their target genes through interaction and nuclear translocation of EYA protein (PubMed:10490620).
Acts synergistically with SIX1 to regulate target genes involved in formation of various organs, including muscle, kidney, gonad, ganglia, olfactory epithelium and cranial skeleton. Plays a role in several important steps of muscle development. Controls the genesis of hypaxial myogenic progenitors in the dermomyotome by transactivating PAX3 and the delamination and migration of the hypaxial precursors from the ventral lip to the limb buds through the transactivation of PAX3, MET and LBX1 (PubMed:15788460).
Controls myoblast determination by transactivating MYF5, MYOD1 and MYF6 (PubMed:15788460, PubMed:17592144).
Controls somitic differentiation in myocyte through MYOG transactivation (PubMed:15788460).
Plays a role in synaptogenesis and sarcomere organization by participating in myofiber specialization during embryogenesis by activating fast muscle program in the primary myotome resulting in an up-regulation of fast muscle genes, including ATP2A1, MYL1 and TNNT3 (PubMed:19962975, PubMed:21884692).
Simultaneously, is also able to activate inhibitors of slow muscle genes, such as SOX6, HRASLS, and HDAC4, thereby restricting the activation of the slow muscle genes (PubMed:21884692).
During muscle regeneration, negatively regulates differentiation of muscle satellite cells through down-regulation of MYOG expression (PubMed:20696153).
During kidney development regulates the early stages of metanephros development and ureteric bud formation through regulation of GDNF, SALL1, PAX8 and PAX2 expression (PubMed:17300925).
Plays a role in gonad development by regulating both testis determination and size determination. In gonadal sex determination, transactivates ZFPM2 by binding a MEF3 consensus sequence, resulting in SRY up-regulation. In gonadal size determination, transactivates NR5A1 by binding a MEF3 consensus sequence resulting in gonadal precursor cell formation regulation (PubMed:23987514).
During olfactory development mediates the specification and patterning of olfactory placode through fibroblast growth factor and BMP4 signaling pathways and also regulates epithelial cell proliferation during placode formation (PubMed:19027001).
Promotes survival of sensory neurons during early trigeminal gangliogenesis (PubMed:16938278).
In the developing dorsal root ganglia, up-regulates SLC12A2 transcription (PubMed:15955062).
Regulates early thymus/parathyroid organogenesis through regulation of GCM2 and FOXN1 expression (PubMed:16530750).
Forms gustatory papillae during development of the tongue (PubMed:21978088).
Also plays a role during embryonic cranial skeleton morphogenesis (PubMed:20515681).

Features

Showing features for dna binding.

TypeIDPosition(s)Description
DNA binding216-275Homeobox

GO annotations

AspectTerm
Cellular Componentcytoplasm
Cellular Componentnucleus
Cellular Componenttranscription regulator complex
Molecular FunctionDNA binding
Molecular FunctionDNA-binding transcription activator activity, RNA polymerase II-specific
Molecular FunctionDNA-binding transcription factor activity
Molecular FunctionDNA-binding transcription factor activity, RNA polymerase II-specific
Molecular FunctionRNA polymerase II cis-regulatory region sequence-specific DNA binding
Molecular Functionsequence-specific DNA binding
Biological Processembryonic cranial skeleton morphogenesis
Biological Processembryonic skeletal system morphogenesis
Biological Processfungiform papilla morphogenesis
Biological Processgeneration of neurons
Biological Processinner ear morphogenesis
Biological Processmale gonad development
Biological Processmale sex determination
Biological Processmale sex differentiation
Biological Processmetanephric mesenchyme development
Biological Processmyoblast migration
Biological Processmyotome development
Biological Processnegative regulation of apoptotic process
Biological Processnegative regulation of DNA-templated transcription
Biological Processnegative regulation of neuron apoptotic process
Biological Processnegative regulation of satellite cell differentiation
Biological Processolfactory placode formation
Biological Processpharyngeal system development
Biological Processpositive regulation of branching involved in ureteric bud morphogenesis
Biological Processpositive regulation of DNA-templated transcription
Biological Processpositive regulation of transcription by RNA polymerase II
Biological Processpositive regulation of ureteric bud formation
Biological Processprotein localization to nucleus
Biological Processregulation of branch elongation involved in ureteric bud branching
Biological Processregulation of epithelial cell proliferation
Biological Processregulation of gene expression
Biological Processregulation of protein localization
Biological Processregulation of synaptic assembly at neuromuscular junction
Biological Processregulation of transcription by RNA polymerase II
Biological Processsarcomere organization
Biological Processskeletal muscle fiber differentiation
Biological Processskeletal muscle tissue development
Biological Processthymus development
Biological Processtongue development
Biological Processtrigeminal ganglion development

Keywords

Names & Taxonomy

Protein names

  • Recommended name
    Homeobox protein SIX4
  • Alternative names
    • Sine oculis homeobox homolog 4
    • Skeletal muscle-specific ARE-binding protein AREC3

Gene names

    • Name
      Six4
    • Synonyms
      Arec3

Organism names

  • Taxonomic identifier
  • Strain
    • BALB/cJ
  • Taxonomic lineage
    Eukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Mus > Mus

Accessions

  • Primary accession
    Q61321
  • Secondary accessions
    • B2RQH3
    • Q61322
    • Q61323

Proteomes

Organism-specific databases

Subcellular Location

Keywords

Phenotypes & Variants

Disruption phenotype

Mice are viable and fertile; no gross morphological or histological abnormalities, or defects in hearing ability are detected in homozygous mice (PubMed:11313460).
Double homozygous SIX1 and SIX4 knockout mice die soon after birth and show developmental defects in various organs (PubMed:15955062).
Double homozygous SIX1 and SIX4 knockout mice causes severe defects in the trigeminal ganglia (PubMed:16938278).
Double homozygous SIX1 and SIX4 knockout mice exhibit more severe kidney phenotypes than the SIX1 knockout mice. Double homozygous SIX1 and SIX4 knockout embryos show distinct morphological changes: fusion of the lateral lingual swellings is delayed, and the tongue is poorly developed. The primordia of fungiform papillae appears earlier, and the papillae rapidly increases in size; thus fusion of each papilla is evident. The circumvallate papillae show severe defects: invagination of the trenches starts asymmetrically, which results in longer and shorter trenches (PubMed:21978088).
Double homozygous SIX1 and SIX4 knockout neonatal mice have a male-to-female sex-reversal phenotype in XY mutant gonads (PubMed:23987514).
Double homozygous SIX1 and SIX4 knockout neonatal mice are characterized by severe craniofacial and rib defects, and general muscle hypoplasia (PubMed:15788460).

Variants

We now provide the "Disease & Variants" viewer in its own tab.

The viewer provides 38 variants from UniProt as well as other sources including ClinVar and dbSNP.

Go to variant viewer

PTM/Processing

Features

Showing features for initiator methionine, modified residue, chain.

TypeIDPosition(s)Description
Initiator methionine1Removed
Modified residue2N-acetylserine
ChainPRO_00000493042-775Homeobox protein SIX4
Modified residue634Phosphoserine

Keywords

Proteomic databases

PTM databases

Expression

Tissue specificity

Mainly expressed in the skeletal muscle (isoform 1 and isoform 2 but not isoform 3), and weakly in the heart. Also found in the retina and the distal tube of kidney. Expressed in skeletal muscle, nasal epithelium, cochlea, parathyroid and salivary gland (PubMed:11313460).
Expressed in muscle satellite cells of normal and regenerating muscles (PubMed:20696153).

Developmental stage

At 8.5 dpc expressed at the surface ectoderm outside the neural folds, somites, presomitic mesoderm. At 9.5 dpc expressed at the nasal and otic placodes, cranial ganglia, branchial arches, somites (dermamyotomes and sclerotomes). At 10.5-11.5 dpc expressed at the nasal pits, otic vesicles, cranial ganglia, dorsal root ganglia, branchial arches, somites, myotomes, limb mesenchyme, notochord, mesonephros. At 12.5-13.5 dpc expressed in skeletal muscles, mesenchyme in limbs and digits, nasal epithelium, inner ear (PubMed:11313460).
Weakly expressed in the nephrogenic cord on 9.5 dpc and in the metanephric mesenchyme on 10.5 dpc (PubMed:17300925).
At 11.5 dpc expressed in the epithelium of the lateral lingual swellings, and in the tongue epithelium, mesenchyme, and muscles at 12.5 dpc. In the fungiform papillae, expressed in the epithelium at 14-16.5 dpc. In the circumvallate and foliate papillae, expression is observed in the trench wall of these papillae at 15.5 dpc-P0 (PubMed:21978088).
At 11.5 dpc mainly found in limbs, and somites, where is expressed in the dorsal root ganglion, myotomes, and ventral and dorsal dermomyotomal lips (PubMed:15788460).
Expressed in a wide domain of the ectoderm in the presumptive olfactory region and in the thickened olfactory placode. Expressed in the peripheral precursors of the pit. At 12.5 dpc-14.5 dpc, expression become progressively restricted to the apical and basal progenitors.Also expressed strongly in the preplacodal region at 8.0 dpc and in the presumptive olfactory ectoderm at 9.0 dpc (PubMed:19027001).
At 10.5 dpc expressed in the progenitors of the dermomyotome and in the myocytes (PubMed:19962975).

Gene expression databases

Interaction

Subunit

Interacts with EYA3; acts cooperatively with EYA3 to transactivate target genes through interaction and nuclear translocation of EYA3 protein (PubMed:10490620, PubMed:12215533).

Binary interactions

TypeEntry 1Entry 2Number of experimentsIntact
BINARY Q61321Kdm6a O705462EBI-986524, EBI-1573712

Protein-protein interaction databases

Miscellaneous

Structure

Family & Domains

Features

Showing features for region, compositional bias.

TypeIDPosition(s)Description
Region1-76Disordered
Region263-313Disordered
Compositional bias285-299Basic and acidic residues
Region582-775Transactivation domain

Sequence similarities

Belongs to the SIX/Sine oculis homeobox family.

Keywords

Phylogenomic databases

Family and domain databases

Sequence & Isoforms

Align isoforms (3)
  • Sequence status
    Complete

This entry describes 3 isoforms produced by Alternative splicing. Additional isoforms seem to exist.

Q61321-1

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.

  • Name
    1
  • Synonyms
    SM
  • See also
    sequence in UniParc or sequence clusters in UniRef
  • Length
    775
  • Mass (Da)
    82,263
  • Last updated
    1996-11-01 v1
  • Checksum
    B06EBB64E04E5061
MSSSSPTGQIASAADIKQENGMESASEGQEAHREVAGGAAAGLSPPAPAPFPLEPGDAAAASRVSREEGAAAAGAADQVQLHSELLGRHQHAAAAQPPLAFSPDHVACVCEALQQGGNLDRLARFLWSLPQSDLLRGNESLLKARALVAFHQGIYPELYSILESHSFESANHPLLQQLWYKARYTEAERARGRPLGAVDKYRLRRKFPLPRTIWDGEETVYCFKEKSRNALKELYKQNRYPSPAEKRHLAKITGLSLTQVSNWFKNRRQRDRNPSETQSKSESDGNPSTEDESSKGHEDLSPHPLSGASDGVTNLSLSSHVEPVYMQQIGNAKISLSSSGVLLNGSLVPASTSPVFLNGNSFIQGHNGVILNGLNVGNTQTVSLNPPKMSSNIVGNGIAMTDILGSTSQDVKEFKVLQSSAVNSAATTSYSPSAPVSFPGLIPCTEVKREGIQTVASQDGGSVVTFTTPVQINQYGIVQIPNSGANGQFLNGSIGFSPLQLPPVSVAASQGNLSVTPSTSDGSTFTSEPATVQHGKLFLSPLTPSAVVYTVPNSGQTVGAVKQEGLERGLVFSQLMPVNHSAQVNASLSSENLSGSGLHPLTSSLVNVSAAHGFSLTPPTLLNPTELNPDLAESQPVSAPVASKCTVSSVSNTNYATLQNCSLIPGQDLLSGPMTQAALGEIVPTAEEQVSHASTAVHQDFVREQRLVLQSVPNIKENFLQNSENKATNNLMMLDSKSKYVLDGMVEAGCEDLGTDKKELAKLQTVQLDEDMQDL

Q61321-2

  • Name
    2
  • Synonyms
    M18
  • Note
    Incomplete sequence.
  • See also
    sequence in UniParc or sequence clusters in UniRef
  • Differences from canonical
    • 1-9: MSSSSPTGQ → QKAAIRLHYFALAAILM
    • 37-100: Missing

Q61321-3

  • Name
    3
  • Synonyms
    M8
  • Note
    Incomplete sequence.
  • See also
    sequence in UniParc or sequence clusters in UniRef
  • Differences from canonical
    • 1-9: MSSSSPTGQ → QKAAIRLHYFALAAILM
    • 188-319: ERARGRPLGAVDKYRLRRKFPLPRTIWDGEETVYCFKEKSRNALKELYKQNRYPSPAEKRHLAKITGLSLTQVSNWFKNRRQRDRNPSETQSKSESDGNPSTEDESSKGHEDLSPHPLSGASDGVTNLSLSS → AGNSPCPAPSGTARRRCIVSRRSRATRSRSSTSRIATPRRLRSGTWPRSPASPSPRSATGSRTGGSVTETPPRPSPKANRMATPVPRMNPARDMRICLLIHFQAHLMASPTSASLATWSQYICNKLEMLRYH
    • 320-775: Missing

Computationally mapped potential isoform sequences

There is 1 potential isoform mapped to this entry

View all
EntryEntry nameGene nameLength
H3BL91H3BL91_MOUSESix4518

Features

Showing features for alternative sequence, compositional bias.

TypeIDPosition(s)Description
Alternative sequenceVSP_0022931-9in isoform 2 and isoform 3
Alternative sequenceVSP_00229437-100in isoform 2
Alternative sequenceVSP_002295188-319in isoform 3
Compositional bias285-299Basic and acidic residues
Alternative sequenceVSP_002296320-775in isoform 3

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
D50416
EMBL· GenBank· DDBJ
BAA08915.1
EMBL· GenBank· DDBJ
mRNA
D50417
EMBL· GenBank· DDBJ
BAA08916.1
EMBL· GenBank· DDBJ
mRNA
D50418
EMBL· GenBank· DDBJ
BAA08917.1
EMBL· GenBank· DDBJ
mRNA
BC137931
EMBL· GenBank· DDBJ
AAI37932.1
EMBL· GenBank· DDBJ
mRNA
BC137934
EMBL· GenBank· DDBJ
AAI37935.1
EMBL· GenBank· DDBJ
mRNA

Genome annotation databases

Similar Proteins

Disclaimer

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