Reviewed, UniProtKB/Swiss-Prot Q62231 (SIX1_MOUSE)

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)

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus

Protein attributes

Sequence length	284 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
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.
Subunit structure	Interacts with DACH1 and EYA3. Interacts with EYA2 By similarity.
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
Gene Ontology (GO)
Biological process	branching involved in ureteric bud morphogenesis Ref.6 Inferred from genetic interaction. Source: MGI embryonic skeletal system morphogenesis Inferred from genetic interaction. Source: MGI epithelial cell differentiation Inferred from mutant phenotype. Source: MGI induction of an organ Ref.6 Inferred from mutant phenotype. Source: MGI inner ear morphogenesis Inferred from genetic interaction. Source: MGI myoblast migration Inferred from genetic interaction. Source: MGI pattern specification process Inferred from genetic interaction. Source: MGI positive regulation of transcription from RNA polymerase II promoter Inferred from direct assay. Source: MGI regulation of neuron differentiation Inferred from mutant phenotype. Source: MGI thymus development Inferred from genetic interaction. Source: MGI thyroid gland development Inferred from mutant phenotype. Source: MGI transcription Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	transcription factor complex Ref.7 Inferred from direct assay. Source: MGI
Molecular function	protein binding Inferred from physical interaction. Source: IntAct sequence-specific DNA binding Ref.4 Inferred from direct assay. Source: MGI transcription factor activity Inferred from direct assay. Source: MGI
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Eya1	P97767	2	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)
	Q62231-1 [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: 7720577] [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: 15489334] [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: 11978764] [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: 9826681] [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: 12215533] [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: 12783782] [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: 14628042] [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: 14695375] [Abstract] Cited for: FUNCTION, DEVELOPMENTAL STAGE.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBLGenBankDDBJ	X80339 mRNA. Translation: CAA56585.1. BC023304 mRNA. Translation: AAH23304.1.
IPI	IPI00229876.
PIR	S60751.
RefSeq	NP_033215.2.
UniGene	Mm.4645
3D structure databases
HSSP	HSSP built from PDB template 1B72 based on UniProtKB P40424.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q62231. 1 interaction.
Genome annotation databases
Ensembl	ENSMUSG00000051367. Mus musculus. [Contig view]
GeneID	20471.
Organism-specific databases
MGI	MGI:102780. Six1.
Phylogenomic databases
HOGENOM	Q62231.
HOVERGEN	Q62231.
OMA	Q62231. PRQAPAM.
Gene expression databases
ArrayExpress	Q62231.
Bgee	Q62231.
GermOnline	ENSMUSG00000051367. Mus musculus.
Family and domain databases
InterPro	IPR001356. Homeobox. IPR017970. Homeobox_CS. IPR012287. Homeodomain-rel. [Graphical view]
Gene3D	G3DSA:1.10.10.60. Homeodomain-rel. 1 hit.
Pfam	PF00046. Homeobox. 1 hit. [Graphical view]
ProDom	PD000010. Homeobox. 1 hit. [Graphical view] [Entries sharing at least one domain]
SMART	SM00389. HOX. 1 hit. [Graphical view]
PROSITE	PS00027. HOMEOBOX_1. 1 hit. PS50071. HOMEOBOX_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
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:	June 16, 2009
This is version 76 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)