Q62231 (SIX1_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Homeobox protein SIX1

Alternative name(s):
Sine oculis homeobox homolog 1

Gene names

Name:

Six1

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	284 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Transcription factor that is involved in regulation of organogenesis. Seems to be required for development of kidney, muscle and inner ear. Seems to be involved in later steps of myogenic differentiation. May be involved in limb tendon and ligament development. Binds a 5'-TCA[AG][AG]TTNC-3' motif present in the MEF3 element in the myogenin promoter. Thought to be regulated by association with Dach and Eya proteins. Acts as activator of the IGFBP5 promoter, probably coactivated by EYA2. Repression of precursor cell proliferation in myoblasts is switched to activation through recruitment of EYA3 phosphatase to the SIX1-DACH1 complex. During myogenesis, seems to act together with EYA2 and DACH2 By similarity. Ref.3 Ref.5 Ref.6 Ref.7 Ref.9
Subunit structure	Interacts with DACH1 and EYA3. Interacts with EYA2 By similarity. Ref.3 Ref.5 Ref.7
Subcellular location	Nucleus.
Tissue specificity	Expressed in phalangeal tendons and in skeletal muscle and in head and body mesenchyme.
Developmental stage	First expressed at E8.2-8.5 of embryo development in the anterior head mesoderm and developing pharyngeal pouches. Expression in the developing limb begins at E11 and is more pronounced dorsally. It progresses into the developing phalanges at E13.5. In the developing inner ear detected in the otic placode and the surrounding surface ectoderm at E8.5. Expression became prominent at the invaginating otic pit and the nascent otic vesicle at E9.5. At E10.5, expression was limited to the ventral half of the otic vesicle. Subsequently, the expression became gradually restricted to the cochlear region at E11.5 and E12.5. At later stages detected exclusively in the cochlea at E14.5, and the expression in the cochlear duct persisted in the neonate. In the developing kidney, is expressed in the uninduced metanephric mesenchyme at E10.5 and in the induced mesenchyme around the ureteric bud at E11.5. At E17.5 to P0, expression becomes restricted to a subpopulation of collecting tubule epithelial cells. Ref.6 Ref.9
Disruption phenotype	Mice show failure in renal organogenesis, a severe reduction of most migratory hypaxoal muscles including those of the forelimb, diaphragm and tongue, severe rib-cage deformation, and loss of inner ear structures. PAX2, SIX2 and SALL1 expression is markedly reduced in the metanephric mesenchyme at E10.5 during kidney development. SIX1 and EYA1 double-deficient mice show defects in kidney development, complete absence of hypaxial muscle, severe reduction in epaxial muscle and a 5-10-fold by volume smaller pituarity than the wild-type gland. Ref.6
Sequence similarities	Belongs to the SIX/Sine oculis homeobox family. Contains 1 homeobox DNA-binding domain.

Ontologies

Keywords
Biological process	Transcription Transcription regulation
Cellular component	Nucleus
Domain	Homeobox
Ligand	DNA-binding
Molecular function	Activator Developmental protein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	aorta morphogenesis Inferred from genetic interaction PubMed 21364285. Source: MGI branching involved in ureteric bud morphogenesis Inferred from genetic interaction Ref.6. Source: MGI cochlea morphogenesis Inferred from mutant phenotype PubMed 12874121. Source: MGI embryonic cranial skeleton morphogenesis Inferred from genetic interaction PubMed 20515681. Source: MGI epithelial cell differentiation Inferred from mutant phenotype PubMed 16530750. Source: MGI facial nerve morphogenesis Inferred from mutant phenotype PubMed 12874121. Source: MGI mesonephric tubule formation Inferred from mutant phenotype PubMed 17300925. Source: UniProtKB metanephric mesenchyme development Inferred from mutant phenotype PubMed 17300925. Source: UniProtKB middle ear morphogenesis Inferred from mutant phenotype PubMed 12874121. Source: MGI myoblast migration Inferred from genetic interaction PubMed 15788460. Source: MGI negative regulation of branching involved in ureteric bud morphogenesis Inferred from mutant phenotype PubMed 21281623. Source: MGI negative regulation of neuron apoptotic process Inferred from mutant phenotype PubMed 16938278. Source: UniProtKB negative regulation of transcription from RNA polymerase II promoter Inferred from direct assay PubMed 21281623. Source: MGI neuron fate specification Inferred from genetic interaction PubMed 22513373. Source: MGI organ induction Inferred from mutant phenotype Ref.6. Source: MGI otic vesicle development Inferred from mutant phenotype PubMed 16916509. Source: MGI outflow tract morphogenesis Inferred from genetic interaction PubMed 21364285. Source: MGI pattern specification process Inferred from mutant phenotype PubMed 16916509. Source: MGI pharyngeal system development Inferred from genetic interaction PubMed 21364285. Source: MGI positive regulation of branching involved in ureteric bud morphogenesis Inferred from mutant phenotype PubMed 17300925. Source: UniProtKB positive regulation of mesenchymal cell proliferation involved in ureter development Inferred from genetic interaction PubMed 20110314. Source: MGI positive regulation of secondary heart field cardioblast proliferation Inferred from genetic interaction PubMed 21364285. Source: MGI positive regulation of transcription from RNA polymerase II promoter Inferred from direct assay PubMed 15955062. Source: MGI positive regulation of ureteric bud formation Inferred from mutant phenotype PubMed 17300925. Source: UniProtKB protein localization to nucleus Inferred from electronic annotation. Source: Compara regulation of branch elongation involved in ureteric bud branching Inferred from mutant phenotype PubMed 17300925. Source: UniProtKB regulation of neuron differentiation Inferred from mutant phenotype PubMed 15496442. Source: MGI regulation of protein localization Inferred from genetic interaction PubMed 21884692. Source: MGI regulation of synaptic growth at neuromuscular junction Inferred from genetic interaction PubMed 21884692. Source: MGI sensory perception of sound Inferred from mutant phenotype PubMed 12874121. Source: MGI skeletal muscle tissue development Inferred from genetic interaction PubMed 15788460. Source: MGI thymus development Inferred from mutant phenotype PubMed 16530750. Source: MGI thyroid gland development Inferred from mutant phenotype PubMed 16530750. Source: MGI transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW ureter smooth muscle cell differentiation Inferred from mutant phenotype PubMed 20110314. Source: MGI
Cellular_component	nucleolus Inferred from electronic annotation. Source: Compara transcription factor complex Inferred from direct assay Ref.7. Source: MGI
Molecular_function	chromatin binding Inferred from genetic interaction PubMed 19008232. Source: MGI sequence-specific DNA binding Inferred from direct assay PubMed 17098221Ref.4. Source: MGI sequence-specific DNA binding transcription factor activity Inferred from direct assay PubMed 15955062. Source: MGI transcription regulatory region DNA binding Inferred from electronic annotation. Source: Compara
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Eya1	P97767	3	EBI-1368483,EBI-1368503

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 284	284	Homeobox protein SIX1		PRO_0000049296
Regions
	DNA binding	124 – 183	60	Homeobox Ref.4
Experimental info
	Sequence conflict	12 – 14	3	EQV → GQG in CAA56585. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Q62231 [UniParc]. Last modified April 13, 2004. Version 2. Checksum: 4A6F88000FB9F8EB	FASTA	284	32,210
	10 20 30 40 50 60 MSMLPSFGFT QEQVACVCEV LQQGGNLERL GRFLWSLPAC DHLHKNESVL KAKAVVAFHR 70 80 90 100 110 120 GNFRELYKIL ESHQFSPHNH PKLQQLWLKA HYVEAEKLRG RPLGAVGKYR VRRKFPLPRT 130 140 150 160 170 180 IWDGEETSYC FKEKSRGVLR EWYAHNPYPS PREKRELAEA TGLTTTQVSN WFKNRRQRDR 190 200 210 220 230 240 AAEAKERENT ENNNSSSNKQ NQLSPLEGGK PLMSSSEEEF SPPQSPDQNS VLLLQSNMGH 250 260 270 280 ARSSNYSLPG LTASQPSHGL QAHQHQLQDS LLGPLTSSLV DLGS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Homeobox genes and connective tissue patterning." Oliver G., Wehr R., Jenkins N.A., Copeland N.G., Cheyette B.N.R., Hartenstein V., Zipursky S.L., Gruss P. Development 121:693-705(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 12-284. Strain: C57BL/6J. Tissue: Embryo.
[2]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: FVB/N. Tissue: Salivary gland.
[3]	"Identification of transcriptional targets for Six5: implication for the pathogenesis of myotonic dystrophy type 1." Sato S., Nakamura M., Cho D.H., Tapscott S.J., Ozaki H., Kawakami K. Hum. Mol. Genet. 11:1045-1058(2002) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH EYA2.
[4]	"Expression of myogenin during embryogenesis is controlled by Six/sine oculis homeoproteins through a conserved MEF3 binding site." Spitz F., Demignon J., Porteu A., Kahn A., Concordet J.P., Daegelen D., Maire P. Proc. Natl. Acad. Sci. U.S.A. 95:14220-14225(1998) [PubMed] [Europe PMC] [Abstract] Cited for: DNA-BINDING.
[5]	"Molecular interaction and synergistic activation of a promoter by Six, Eya, and Dach proteins mediated through CREB binding protein." Ikeda K., Watanabe Y., Ohto H., Kawakami K. Mol. Cell. Biol. 22:6759-6766(2002) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH EYA3.
[6]	"Six1 is required for the early organogenesis of mammalian kidney." Xu P.X., Zheng W., Huang L., Maire P., Laclef C., Silvius D. Development 130:3085-3094(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, DEVELOPMENTAL STAGE, DISRUPTION PHENOTYPE.
[7]	"Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis." Li X., Oghi K.A., Zhang J., Krones A., Bush K.T., Glass C.K., Nigam S.K., Aggarwal A.K., Maas R., Rose D.W., Rosenfeld M.G. Nature 426:247-254(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH DACH1 AND EYA3.
[8]	Erratum Li X., Oghi K.A., Zhang J., Krones A., Bush K.T., Glass C.K., Nigam S.K., Aggarwal A.K., Maas R., Rose D.W., Rosenfeld M.G. Nature 427:265-265(2004)
[9]	"Six1 controls patterning of the mouse otic vesicle." Ozaki H., Nakamura K., Funahashi J., Ikeda K., Yamada G., Tokano H., Okamura H.O., Kitamura K., Muto S., Kotaki H., Sudo K., Horai R., Iwakura Y., Kawakami K. Development 131:551-562(2004) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, DEVELOPMENTAL STAGE.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	X80339 mRNA. Translation: CAA56585.1. BC023304 mRNA. Translation: AAH23304.1.
IPI	IPI00229876.
PIR	S60751.
RefSeq	NP_033215.2. NM_009189.3.
UniGene	Mm.4645.
3D structure databases
ProteinModelPortal	Q62231.
SMR	Q62231. Positions 131-178.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q62231. 1 interaction.
PTM databases
PhosphoSite	Q62231.
Proteomic databases
PRIDE	Q62231.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000050029; ENSMUSP00000059026; ENSMUSG00000051367.
GeneID	20471.
KEGG	mmu:20471.
Organism-specific databases
CTD	6495.
MGI	MGI:102780. Six1.
Phylogenomic databases
eggNOG	NOG289502.
GeneTree	ENSGT00540000070251.
HOGENOM	HOG000261680.
HOVERGEN	HBG003609.
InParanoid	Q62231.
KO	K15614.
OMA	GNLSHAR.
OrthoDB	EOG4RJG27.
Gene expression databases
ArrayExpress	Q62231.
Bgee	Q62231.
Genevestigator	Q62231.
GermOnline	ENSMUSG00000051367. Mus musculus.
Family and domain databases
Gene3D	1.10.10.60. 1 hit.
InterPro	IPR017970. Homeobox_CS. IPR001356. Homeodomain. IPR009057. Homeodomain-like. [Graphical view]
Pfam	PF00046. Homeobox. 1 hit. [Graphical view]
SMART	SM00389. HOX. 1 hit. [Graphical view]
SUPFAM	SSF46689. Homeodomain_like. 1 hit.
PROSITE	PS00027. HOMEOBOX_1. 1 hit. PS50071. HOMEOBOX_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	298579.
SOURCE	Search...

Entry information

Entry name

SIX1_MOUSE

Accession

Primary (citable) accession number: Q62231
Secondary accession number(s): Q8CIL7

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1997
Last sequence update:	April 13, 2004
Last modified:	May 1, 2013
This is version 115 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program