SIX2_MOUSE
ID SIX2_MOUSE Reviewed; 296 AA.
AC Q62232; P70179;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 15-JUL-1998, sequence version 2.
DT 03-AUG-2022, entry version 159.
DE RecName: Full=Homeobox protein SIX2;
DE AltName: Full=Sine oculis homeobox homolog 2;
GN Name=Six2;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND FUNCTION.
RC STRAIN=C57BL/6J; TISSUE=Embryo;
RX PubMed=7720577; DOI=10.1242/dev.121.3.693;
RA Oliver G., Wehr R., Jenkins N.A., Copeland N.G., Cheyette B.N.R.,
RA Hartenstein V., Zipursky S.L., Gruss P.;
RT "Homeobox genes and connective tissue patterning.";
RL Development 121:693-705(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND SUBCELLULAR LOCATION.
RC STRAIN=BALB/cJ;
RX PubMed=8814301; DOI=10.1016/0014-5793(96)00899-x;
RA Kawakami K., Ohto H., Takizawa T., Saito T.;
RT "Identification and expression of Six family genes in mouse retina.";
RL FEBS Lett. 393:259-263(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Embryo;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP INTERACTION WITH EYA1.
RX PubMed=11734542; DOI=10.1093/hmg/10.24.2775;
RA Buller C., Xu X., Marquis V., Schwanke R., Xu P.X.;
RT "Molecular effects of Eya1 domain mutations causing organ defects in BOR
RT syndrome.";
RL Hum. Mol. Genet. 10:2775-2781(2001).
RN [5]
RP INTERACTION WITH EYA3.
RX PubMed=12215533; DOI=10.1128/mcb.22.19.6759-6766.2002;
RA Ikeda K., Watanabe Y., Ohto H., Kawakami K.;
RT "Molecular interaction and synergistic activation of a promoter by Six,
RT Eya, and Dach proteins mediated through CREB binding protein.";
RL Mol. Cell. Biol. 22:6759-6766(2002).
RN [6]
RP FUNCTION IN KIDNEY DEVELOPMENT, DEVELOPMENTAL STAGE, AND DISRUPTION
RP PHENOTYPE.
RX PubMed=17036046; DOI=10.1038/sj.emboj.7601381;
RA Self M., Lagutin O.V., Bowling B., Hendrix J., Cai Y., Dressler G.R.,
RA Oliver G.;
RT "Six2 is required for suppression of nephrogenesis and progenitor renewal
RT in the developing kidney.";
RL EMBO J. 25:5214-5228(2006).
RN [7]
RP FUNCTION IN NEPHRON DEVELOPMENT.
RX PubMed=18682239; DOI=10.1016/j.stem.2008.05.020;
RA Kobayashi A., Valerius M.T., Mugford J.W., Carroll T.J., Self M.,
RA Oliver G., McMahon A.P.;
RT "Six2 defines and regulates a multipotent self-renewing nephron progenitor
RT population throughout mammalian kidney development.";
RL Cell Stem Cell 3:169-181(2008).
RN [8]
RP FUNCTION IN BRANCHIAL ARCH DEVELOPMENT, AND INDUCTION.
RX PubMed=18321982; DOI=10.1242/dev.017624;
RA Kutejova E., Engist B., Self M., Oliver G., Kirilenko P., Bobola N.;
RT "Six2 functions redundantly immediately downstream of Hoxa2.";
RL Development 135:1463-1470(2008).
RN [9]
RP FUNCTION IN STOMACH MORPHOGENESIS, AND DEVELOPMENTAL STAGE.
RX PubMed=19660448; DOI=10.1016/j.ydbio.2009.07.039;
RA Self M., Geng X., Oliver G.;
RT "Six2 activity is required for the formation of the mammalian pyloric
RT sphincter.";
RL Dev. Biol. 334:409-417(2009).
RN [10]
RP INDUCTION.
RX PubMed=19716816; DOI=10.1016/j.ydbio.2009.08.020;
RA Yallowitz A.R., Gong K.Q., Swinehart I.T., Nelson L.T., Wellik D.M.;
RT "Non-homeodomain regions of Hox proteins mediate activation versus
RT repression of Six2 via a single enhancer site in vivo.";
RL Dev. Biol. 335:156-165(2009).
RN [11]
RP FUNCTION IN CRANIOFACIAL DEVELOPMENT.
RX PubMed=20515681; DOI=10.1016/j.ydbio.2010.05.509;
RA He G., Tavella S., Hanley K.P., Self M., Oliver G., Grifone R., Hanley N.,
RA Ward C., Bobola N.;
RT "Inactivation of Six2 in mouse identifies a novel genetic mechanism
RT controlling development and growth of the cranial base.";
RL Dev. Biol. 344:720-730(2010).
RN [12]
RP FUNCTION IN PROGENITOR CELL PROLIFERATION.
RX PubMed=21350016; DOI=10.1242/dev.057646;
RA Karner C.M., Das A., Ma Z., Self M., Chen C., Lum L., Oliver G.,
RA Carroll T.J.;
RT "Canonical Wnt9b signaling balances progenitor cell expansion and
RT differentiation during kidney development.";
RL Development 138:1247-1257(2011).
RN [13]
RP FUNCTION IN REGULATION OF NEPHRON PROGENITOR RENEWAL, INTERACTION WITH
RP TCF7L2 AND HOXA11, AND INDUCTION.
RX PubMed=22902740; DOI=10.1016/j.devcel.2012.07.008;
RA Park J.S., Ma W., O'Brien L.L., Chung E., Guo J.J., Cheng J.G.,
RA Valerius M.T., McMahon J.A., Wong W.H., McMahon A.P.;
RT "Six2 and Wnt regulate self-renewal and commitment of nephron progenitors
RT through shared gene regulatory networks.";
RL Dev. Cell 23:637-651(2012).
RN [14]
RP FUNCTION IN REGULATION OF NEPHRON PROGENITOR RENEWAL, AND INTERACTION WITH
RP OSR1.
RX PubMed=24598167; DOI=10.1242/dev.103283;
RA Xu J., Liu H., Park J.S., Lan Y., Jiang R.;
RT "Osr1 acts downstream of and interacts synergistically with Six2 to
RT maintain nephron progenitor cells during kidney organogenesis.";
RL Development 141:1442-1452(2014).
CC -!- FUNCTION: Transcription factor that plays an important role in the
CC development of several organs, including kidney, skull and stomach.
CC During kidney development, maintains cap mesenchyme multipotent nephron
CC progenitor cells in an undifferentiated state by opposing the inductive
CC signals emanating from the ureteric bud and cooperates with WNT9B to
CC promote renewing progenitor cells proliferation. Acts through its
CC interaction with TCF7L2 and OSR1 in a canonical Wnt signaling
CC independent manner preventing transcription of differentiation genes in
CC cap mesenchyme such as WNT4. Also acts independently of OSR1 to
CC activate expression of many cap mesenchyme genes, including itself,
CC GDNF and OSR1. During craniofacial development plays a role in growth
CC and elongation of the cranial base through regulation of chondrocyte
CC differentiation (PubMed:20515681). During stomach organogenesis,
CC controls pyloric sphincter formation and mucosal growth through
CC regulation of a gene network including NKX2-5, BMPR1B, BMP4, SOX9 and
CC GREM1 (PubMed:19660448). During branchial arch development, acts to
CC mediate HOXA2 control over the insulin-like growth factor pathway
CC (PubMed:18321982). May also be involved in limb tendon and ligament
CC development (PubMed:7720577). Plays a role in cell proliferation and
CC migration (By similarity). {ECO:0000250|UniProtKB:Q9NPC8,
CC ECO:0000269|PubMed:17036046, ECO:0000269|PubMed:18321982,
CC ECO:0000269|PubMed:18682239, ECO:0000269|PubMed:19660448,
CC ECO:0000269|PubMed:20515681, ECO:0000269|PubMed:21350016,
CC ECO:0000269|PubMed:22902740, ECO:0000269|PubMed:24598167,
CC ECO:0000269|PubMed:7720577}.
CC -!- SUBUNIT: Interacts with TCF7L2; in a canonical Wnt signaling
CC independent manner; prevents transcription of differentiation genes in
CC cap mesenchyme. Interacts with OSR1; form a strong repressor complex
CC with TCF7L2, TLE2 and TLE3 to prevent the activation of Wnt/beta-
CC catenin target genes in the cap mesenchyme. Interacts with HOXA11, EYA1
CC and EYA3. {ECO:0000269|PubMed:11734542, ECO:0000269|PubMed:12215533,
CC ECO:0000269|PubMed:22902740, ECO:0000269|PubMed:24598167}.
CC -!- INTERACTION:
CC Q62232; P97767: Eya1; NbExp=3; IntAct=EBI-1368736, EBI-1368503;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:8814301}.
CC -!- TISSUE SPECIFICITY: Expressed in phalangeal tendons, in smooth muscle
CC and in head and body mesenchyme.
CC -!- DEVELOPMENTAL STAGE: First expressed at 8.5 dpc of embryo development
CC in a restricted mesodermal subpopulation at the anterior hindbrain
CC level. Expression of SIX2 in the developing limb begins at 11 dpc and
CC is more pronounced ventrally. It progresses into the developing
CC phalanges at 12.5 dpc. At 10.5 dpc expressed in the metanephric
CC blastema, which signals the ureteric bud to evaginate from the Wolffian
CC duct. At 11.5 dpc expressed at high levels in the dorsal anephric
CC mesenchyme and is down-regulated where pretubular aggregates will form
CC on the ventral side of the ureteric bud. At 14.5 dpc, expression
CC persists in the peripheral mesenchyme of the renal cortex. At 9.5 dpc,
CC expressed in the splanchnic mesoderm of the stomach anlage. By 10.5
CC dpc, expressed in the mesoderm of the posterior stomach. Expression is
CC seen in the presumptive glandular stomach primordium at 11.5 dpc. At
CC 12.5 dpc, becomes restricted to the mesenchyme of the antral region of
CC the posterior stomach. At 14.5 dpc, expression remains in the antrum,
CC just anterior to the pyloric sphincter. {ECO:0000269|PubMed:17036046,
CC ECO:0000269|PubMed:19660448}.
CC -!- INDUCTION: Down-regulated by CTNNB1 upon differentiarion. Activated by
CC TLX1 in the kidney and repressed by HOXA2 in the branchial arch and
CC facial mesenchyme. {ECO:0000269|PubMed:18321982,
CC ECO:0000269|PubMed:19716816, ECO:0000269|PubMed:22902740}.
CC -!- DISRUPTION PHENOTYPE: Six2 knockout heterozygous mice not exhibit any
CC obvious abnormalities. However, Six2 knockout nullizygous mice die soon
CC after birth. {ECO:0000269|PubMed:17036046}.
CC -!- SIMILARITY: Belongs to the SIX/Sine oculis homeobox family.
CC {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAA56584.1; Type=Erroneous initiation; Evidence={ECO:0000305};
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DR EMBL; X80338; CAA56584.1; ALT_INIT; mRNA.
DR EMBL; D83147; BAA11825.1; -; mRNA.
DR EMBL; BC068021; AAH68021.1; -; mRNA.
DR CCDS; CCDS29007.1; -.
DR PIR; S74253; S74253.
DR RefSeq; NP_035510.1; NM_011380.2.
DR AlphaFoldDB; Q62232; -.
DR SMR; Q62232; -.
DR BioGRID; 203260; 1.
DR IntAct; Q62232; 1.
DR STRING; 10090.ENSMUSP00000125871; -.
DR PhosphoSitePlus; Q62232; -.
DR PaxDb; Q62232; -.
DR PRIDE; Q62232; -.
DR Antibodypedia; 29934; 184 antibodies from 31 providers.
DR DNASU; 20472; -.
DR Ensembl; ENSMUST00000024947; ENSMUSP00000024947; ENSMUSG00000024134.
DR Ensembl; ENSMUST00000163568; ENSMUSP00000125871; ENSMUSG00000024134.
DR GeneID; 20472; -.
DR KEGG; mmu:20472; -.
DR UCSC; uc008duc.2; mouse.
DR CTD; 10736; -.
DR MGI; MGI:102778; Six2.
DR VEuPathDB; HostDB:ENSMUSG00000024134; -.
DR eggNOG; KOG0775; Eukaryota.
DR GeneTree; ENSGT00940000158292; -.
DR HOGENOM; CLU_046914_2_0_1; -.
DR InParanoid; Q62232; -.
DR OMA; SVHHDTI; -.
DR OrthoDB; 1061244at2759; -.
DR PhylomeDB; Q62232; -.
DR TreeFam; TF315545; -.
DR BioGRID-ORCS; 20472; 1 hit in 75 CRISPR screens.
DR PRO; PR:Q62232; -.
DR Proteomes; UP000000589; Chromosome 17.
DR RNAct; Q62232; protein.
DR Bgee; ENSMUSG00000024134; Expressed in undifferentiated genital tubercle and 141 other tissues.
DR Genevisible; Q62232; MM.
DR GO; GO:0005634; C:nucleus; IDA:MGI.
DR GO; GO:0005667; C:transcription regulator complex; IBA:GO_Central.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IDA:NTNU_SB.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:MGI.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IBA:GO_Central.
DR GO; GO:0044877; F:protein-containing complex binding; IDA:UniProtKB.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:NTNU_SB.
DR GO; GO:0043565; F:sequence-specific DNA binding; IDA:MGI.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; ISO:MGI.
DR GO; GO:0008134; F:transcription factor binding; IPI:UniProtKB.
DR GO; GO:0009948; P:anterior/posterior axis specification; IDA:UniProtKB.
DR GO; GO:0016477; P:cell migration; ISS:UniProtKB.
DR GO; GO:0008283; P:cell population proliferation; IMP:MGI.
DR GO; GO:0002062; P:chondrocyte differentiation; IMP:MGI.
DR GO; GO:0072137; P:condensed mesenchymal cell proliferation; IGI:MGI.
DR GO; GO:0048701; P:embryonic cranial skeleton morphogenesis; IMP:MGI.
DR GO; GO:0048557; P:embryonic digestive tract morphogenesis; IMP:UniProtKB.
DR GO; GO:0048704; P:embryonic skeletal system morphogenesis; IGI:MGI.
DR GO; GO:0030855; P:epithelial cell differentiation; IMP:MGI.
DR GO; GO:0001822; P:kidney development; IMP:UniProtKB.
DR GO; GO:0072161; P:mesenchymal cell differentiation involved in kidney development; IMP:UniProtKB.
DR GO; GO:0072038; P:mesenchymal stem cell maintenance involved in nephron morphogenesis; IDA:UniProtKB.
DR GO; GO:0097168; P:mesenchymal stem cell proliferation; IMP:UniProtKB.
DR GO; GO:0003337; P:mesenchymal to epithelial transition involved in metanephros morphogenesis; IEP:UniProtKB.
DR GO; GO:0007501; P:mesodermal cell fate specification; IDA:UniProtKB.
DR GO; GO:0001656; P:metanephros development; IMP:MGI.
DR GO; GO:0042474; P:middle ear morphogenesis; IGI:MGI.
DR GO; GO:0030857; P:negative regulation of epithelial cell differentiation; IMP:MGI.
DR GO; GO:0072006; P:nephron development; IMP:UniProtKB.
DR GO; GO:0072028; P:nephron morphogenesis; IMP:UniProtKB.
DR GO; GO:1902732; P:positive regulation of chondrocyte proliferation; IMP:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:MGI.
DR GO; GO:0006606; P:protein import into nucleus; IDA:MGI.
DR GO; GO:0090189; P:regulation of branching involved in ureteric bud morphogenesis; IMP:UniProtKB.
DR GO; GO:0032330; P:regulation of chondrocyte differentiation; IMP:UniProtKB.
DR GO; GO:0030278; P:regulation of ossification; IMP:UniProtKB.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR CDD; cd00086; homeodomain; 1.
DR InterPro; IPR009057; Homeobox-like_sf.
DR InterPro; IPR017970; Homeobox_CS.
DR InterPro; IPR001356; Homeobox_dom.
DR InterPro; IPR031701; SIX1_SD.
DR Pfam; PF00046; Homeodomain; 1.
DR Pfam; PF16878; SIX1_SD; 1.
DR SMART; SM00389; HOX; 1.
DR SUPFAM; SSF46689; SSF46689; 1.
DR PROSITE; PS00027; HOMEOBOX_1; 1.
DR PROSITE; PS50071; HOMEOBOX_2; 1.
PE 1: Evidence at protein level;
KW Developmental protein; DNA-binding; Homeobox; Nucleus; Reference proteome.
FT CHAIN 1..296
FT /note="Homeobox protein SIX2"
FT /id="PRO_0000049298"
FT DNA_BIND 124..183
FT /note="Homeobox"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00108"
FT REGION 168..284
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 173..192
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 193..234
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 235..262
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT CONFLICT 1..6
FT /note="MSMLPT -> HVHARH (in Ref. 1; CAA56584)"
FT /evidence="ECO:0000305"
FT CONFLICT 105
FT /note="A -> R (in Ref. 1; CAA56584)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 296 AA; 32718 MW; 0FFAB002014D8E60 CRC64;
MSMLPTFGFT QEQVACVCEV LQQGGNIERL GRFLWSLPAC EHLHKNESVL KAKAVVAFHR
GNFRELYKIL ESHQFSPHNH AKLQQLWLKA HYIEAEKLRG RPLGAVGKYR VRRKFPLPRS
IWDGEETSYC FKEKSRSVLR EWYAHNPYPS PREKRELAEA TGLTTTQVSN WFKNRRQRDR
AAEAKERENS ENSNSSSHNP LASSLNGSGK SVLGSSEDEK TPSGTPDHSS SSPALLLSPP
PPPGLPSLHS LGHPPGPSAV PVPVPGGGGA DPLQHHHSLQ DSILNPMSAN LVDLGS
