HAND2_MOUSE
ID HAND2_MOUSE Reviewed; 217 AA.
AC Q61039; Q61100;
DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
DT 10-MAY-2004, sequence version 3.
DT 03-AUG-2022, entry version 192.
DE RecName: Full=Heart- and neural crest derivatives-expressed protein 2;
DE AltName: Full=Deciduum, heart, autonomic nervous system and neural crest derivatives-expressed protein 2;
DE Short=dHAND;
DE AltName: Full=Helix-loop-helix transcription factor expressed in embryo and deciduum;
DE AltName: Full=Thing-2;
GN Name=Hand2; Synonyms=Dhand, Hed, Thing2;
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 [GENOMIC DNA].
RC TISSUE=Embryo;
RX PubMed=8533092; DOI=10.1126/science.270.5244.1995;
RA Srivastava D., Cserjesi P., Olson E.N.;
RT "A subclass of bHLH proteins required for cardiac morphogenesis.";
RL Science 270:1995-1998(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 92-203.
RC STRAIN=129/Sv; TISSUE=Embryoid bodies;
RX PubMed=7671815; DOI=10.1242/dev.121.8.2513;
RA Cross J.C., Flannery M.L., Blanar M.A., Steingrimsson E., Jenkins N.A.,
RA Copeland N.G., Rutter W.J., Werb Z.;
RT "Hxt encodes a basic helix-loop-helix transcription factor that regulates
RT trophoblast cell development.";
RL Development 121:2513-2523(1995).
RN [4]
RP FUNCTION, AND DEVELOPMENTAL STAGE.
RX PubMed=9171826; DOI=10.1038/ng0697-154;
RA Srivastava D., Thomas T., Lin Q., Kirby M.L., Brown D., Olson E.N.;
RT "Regulation of cardiac mesodermal and neural crest development by the bHLH
RT transcription factor, dHAND.";
RL Nat. Genet. 16:154-160(1997).
RN [5]
RP FUNCTION.
RX PubMed=9671575; DOI=10.1242/dev.125.16.3005;
RA Thomas T., Kurihara H., Yamagishi H., Kurihara Y., Yazaki Y., Olson E.N.,
RA Srivastava D.;
RT "A signaling cascade involving endothelin-1, dHAND and msx1 regulates
RT development of neural-crest-derived branchial arch mesenchyme.";
RL Development 125:3005-3014(1998).
RN [6]
RP SUBUNIT.
RX PubMed=10924525; DOI=10.1074/jbc.m005888200;
RA Firulli B.A., Hadzic D.B., McDaid J.R., Firulli A.B.;
RT "The basic helix-loop-helix transcription factors dHAND and eHAND exhibit
RT dimerization characteristics that suggest complex regulation of function.";
RL J. Biol. Chem. 275:33567-33573(2000).
RN [7]
RP FUNCTION, AND DEVELOPMENTAL STAGE.
RX PubMed=10804186; DOI=10.1242/dev.127.11.2461;
RA Charite J., McFadden D.G., Olson E.N.;
RT "The bHLH transcription factor dHAND controls Sonic hedgehog expression and
RT establishment of the zone of polarizing activity during limb development.";
RL Development 127:2461-2470(2000).
RN [8]
RP FUNCTION, AND DEVELOPMENTAL STAGE.
RX PubMed=10769237; DOI=10.1242/dev.127.10.2133;
RA Fernandez-Teran M., Piedra M.E., Kathiriya I.S., Srivastava D.,
RA Rodriguez-Rey J.C., Ros M.A.;
RT "Role of dHAND in the anterior-posterior polarization of the limb bud:
RT implications for the Sonic hedgehog pathway.";
RL Development 127:2133-2142(2000).
CC -!- FUNCTION: Essential for cardiac morphogenesis, particularly for the
CC formation of the right ventricle and of the aortic arch arteries.
CC Required for vascular development and regulation of angiogenesis,
CC possibly through a VEGF signaling pathway. Also plays an important role
CC in limb development, particularly in the establishment of anterior-
CC posterior polarization, acting as an upstream regulator of sonic
CC hedgehog (SHH) induction in the limb bud. Is involved in the
CC development of branchial arches, which give rise to unique structures
CC in the head and neck. Binds DNA on E-box consensus sequence 5'-CANNTG-
CC 3'. {ECO:0000269|PubMed:10769237, ECO:0000269|PubMed:10804186,
CC ECO:0000269|PubMed:9171826, ECO:0000269|PubMed:9671575}.
CC -!- SUBUNIT: Efficient DNA binding requires dimerization with another bHLH
CC protein. Forms homodimers and heterodimers with TCF3 gene products E12
CC and E47, HAND1 and HEY1, HEY2 and HEYL (hairy-related transcription
CC factors). {ECO:0000269|PubMed:10924525}.
CC -!- INTERACTION:
CC Q61039; Q64279: Hand1; NbExp=3; IntAct=EBI-81388, EBI-81361;
CC Q61039; Q99N72: Mcf2; NbExp=3; IntAct=EBI-81388, EBI-641874;
CC Q61039; P15806: Tcf3; NbExp=2; IntAct=EBI-81388, EBI-81370;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00981}.
CC -!- TISSUE SPECIFICITY: Heart and aorta.
CC -!- DEVELOPMENTAL STAGE: High extraembryonic expression is detected at 7.5
CC dpc in the maternally derived deciduum. Also detected along the yolk
CC sac vessels during the process of remodeling at 9.5-10.0 dpc. Within
CC the embryo, detected at 7.5 dpc in the lateral mesoderm including the
CC precardiac mesoderm. On day 8.5 pc expressed throughout the straight
CC heart tube. In the caudal region of the embryo, expressed in the
CC lateral mesoderm at the level of separation of the somatic and
CC splanchnic mesoderm. On day 9.5 pc expressed throughout the developing
CC cardiovascular region, most abundant in the outflow tract and in the
CC first and second aortic arch arteries, and in pharyngeal arches. As the
CC heart loops, the expression becomes restricted to the conotruncus and
CC future right ventricle (endocardium and myocardium). At 10.5 dpc,
CC highly expressed in the branchial arches, as well as in the truncus
CC arteriosus, aortic sac, and the vascular mesenchyme between the third
CC and fourth aortic arch arteries, which later gives rise to vascular
CC smooth muscle cells and to the mesenchyme of the pharyngeal arch. At
CC 13.5 dpc, barely detectable in the heart, but apparent in the neural
CC crest-derived sympathetic trunk and adrenal medulla, a pattern similar
CC to that of HAND1. In the developing limbs, expression is detected in
CC the posterior mesoderm of the buds at 9.5 dpc. It is then progressively
CC down-regulated at the anterior of the limb buds so that a gradient
CC expression along the anterior-posterior axis of the bud is established
CC with higher expression at the posterior border. At later stages of limb
CC development, expression is restricted to the posterior border of the
CC zeugopod and to the posterior autopod. In the autopod, dynamic
CC expression of HAND2 affects the interdigital regions, the lateral
CC borders of the digits and eventually the developing ventral tendons.
CC After 16 dpc, expression decreases throughout the embryo.
CC {ECO:0000269|PubMed:10769237, ECO:0000269|PubMed:10804186,
CC ECO:0000269|PubMed:9171826}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA86274.1; Type=Frameshift; Evidence={ECO:0000305};
CC Sequence=AAC52338.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; U40039; AAC52338.1; ALT_FRAME; Genomic_DNA.
DR EMBL; AK035160; BAC28965.1; -; mRNA.
DR EMBL; U43715; AAA86274.1; ALT_FRAME; mRNA.
DR CCDS; CCDS22315.1; -.
DR RefSeq; NP_034532.3; NM_010402.4.
DR AlphaFoldDB; Q61039; -.
DR SMR; Q61039; -.
DR BioGRID; 200205; 7.
DR IntAct; Q61039; 8.
DR STRING; 10090.ENSMUSP00000044983; -.
DR iPTMnet; Q61039; -.
DR PhosphoSitePlus; Q61039; -.
DR jPOST; Q61039; -.
DR MaxQB; Q61039; -.
DR PaxDb; Q61039; -.
DR PRIDE; Q61039; -.
DR ProteomicsDB; 271390; -.
DR Antibodypedia; 28534; 296 antibodies from 30 providers.
DR DNASU; 15111; -.
DR Ensembl; ENSMUST00000040104; ENSMUSP00000044983; ENSMUSG00000038193.
DR GeneID; 15111; -.
DR KEGG; mmu:15111; -.
DR UCSC; uc009lss.2; mouse.
DR CTD; 9464; -.
DR MGI; MGI:103580; Hand2.
DR VEuPathDB; HostDB:ENSMUSG00000038193; -.
DR eggNOG; KOG4029; Eukaryota.
DR GeneTree; ENSGT00940000160772; -.
DR HOGENOM; CLU_119591_0_0_1; -.
DR InParanoid; Q61039; -.
DR OMA; CHEDSGA; -.
DR OrthoDB; 1449816at2759; -.
DR PhylomeDB; Q61039; -.
DR TreeFam; TF315153; -.
DR BioGRID-ORCS; 15111; 2 hits in 73 CRISPR screens.
DR ChiTaRS; Hand2; mouse.
DR PRO; PR:Q61039; -.
DR Proteomes; UP000000589; Chromosome 8.
DR RNAct; Q61039; protein.
DR Bgee; ENSMUSG00000038193; Expressed in gastrula and 162 other tissues.
DR Genevisible; Q61039; MM.
DR GO; GO:0000785; C:chromatin; ISO:MGI.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IDA:MGI.
DR GO; GO:0032991; C:protein-containing complex; ISO:MGI.
DR GO; GO:0005667; C:transcription regulator complex; IDA:BHF-UCL.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IDA:BHF-UCL.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; TAS:MGI.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISS:BHF-UCL.
DR GO; GO:0070888; F:E-box binding; IDA:MGI.
DR GO; GO:0003680; F:minor groove of adenine-thymine-rich DNA binding; ISO:MGI.
DR GO; GO:0042803; F:protein homodimerization activity; IPI:BHF-UCL.
DR GO; GO:0000977; F:RNA polymerase II transcription regulatory region sequence-specific DNA binding; ISO:MGI.
DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; IPI:BHF-UCL.
DR GO; GO:0043565; F:sequence-specific DNA binding; IGI:MGI.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; ISO:MGI.
DR GO; GO:0001223; F:transcription coactivator binding; ISS:BHF-UCL.
DR GO; GO:0007512; P:adult heart development; IMP:MGI.
DR GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW.
DR GO; GO:0006915; P:apoptotic process; IMP:MGI.
DR GO; GO:0003278; P:apoptotic process involved in heart morphogenesis; IMP:MGI.
DR GO; GO:0055007; P:cardiac muscle cell differentiation; TAS:MGI.
DR GO; GO:0061309; P:cardiac neural crest cell development involved in outflow tract morphogenesis; IMP:BHF-UCL.
DR GO; GO:0003253; P:cardiac neural crest cell migration involved in outflow tract morphogenesis; IMP:MGI.
DR GO; GO:0003219; P:cardiac right ventricle formation; IMP:BHF-UCL.
DR GO; GO:0003215; P:cardiac right ventricle morphogenesis; TAS:MGI.
DR GO; GO:0060536; P:cartilage morphogenesis; IGI:MGI.
DR GO; GO:0061325; P:cell proliferation involved in outflow tract morphogenesis; IMP:MGI.
DR GO; GO:0071407; P:cellular response to organic cyclic compound; IEA:Ensembl.
DR GO; GO:0071300; P:cellular response to retinoic acid; IEA:Ensembl.
DR GO; GO:0060982; P:coronary artery morphogenesis; IMP:MGI.
DR GO; GO:0061371; P:determination of heart left/right asymmetry; IMP:MGI.
DR GO; GO:0032502; P:developmental process; IBA:GO_Central.
DR GO; GO:0042733; P:embryonic digit morphogenesis; IDA:MGI.
DR GO; GO:0048706; P:embryonic skeletal system development; IGI:MGI.
DR GO; GO:1904019; P:epithelial cell apoptotic process; IMP:MGI.
DR GO; GO:0007507; P:heart development; IGI:MGI.
DR GO; GO:0001947; P:heart looping; IMP:MGI.
DR GO; GO:0003007; P:heart morphogenesis; IMP:MGI.
DR GO; GO:0001701; P:in utero embryonic development; IMP:MGI.
DR GO; GO:0010463; P:mesenchymal cell proliferation; IMP:MGI.
DR GO; GO:0060485; P:mesenchyme development; IGI:MGI.
DR GO; GO:0010667; P:negative regulation of cardiac muscle cell apoptotic process; IMP:BHF-UCL.
DR GO; GO:0043392; P:negative regulation of DNA binding; IDA:MGI.
DR GO; GO:0043433; P:negative regulation of DNA-binding transcription factor activity; IDA:MGI.
DR GO; GO:1904036; P:negative regulation of epithelial cell apoptotic process; IMP:MGI.
DR GO; GO:0010629; P:negative regulation of gene expression; ISO:MGI.
DR GO; GO:0045668; P:negative regulation of osteoblast differentiation; IDA:MGI.
DR GO; GO:0014032; P:neural crest cell development; IMP:MGI.
DR GO; GO:0042475; P:odontogenesis of dentin-containing tooth; IGI:MGI.
DR GO; GO:0001649; P:osteoblast differentiation; IMP:MGI.
DR GO; GO:0048935; P:peripheral nervous system neuron development; IDA:MGI.
DR GO; GO:0010613; P:positive regulation of cardiac muscle hypertrophy; ISO:MGI.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; ISO:MGI.
DR GO; GO:0010628; P:positive regulation of gene expression; ISO:MGI.
DR GO; GO:1900745; P:positive regulation of p38MAPK cascade; ISO:MGI.
DR GO; GO:2000764; P:positive regulation of semaphorin-plexin signaling pathway involved in outflow tract morphogenesis; IMP:BHF-UCL.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:BHF-UCL.
DR GO; GO:2000763; P:positive regulation of transcription from RNA polymerase II promoter involved in norepinephrine biosynthetic process; IMP:BHF-UCL.
DR GO; GO:2000679; P:positive regulation of transcription regulatory region DNA binding; ISO:MGI.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:MGI.
DR GO; GO:1903929; P:primary palate development; IMP:MGI.
DR GO; GO:0003266; P:regulation of secondary heart field cardioblast proliferation; IMP:BHF-UCL.
DR GO; GO:0034103; P:regulation of tissue remodeling; ISO:MGI.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; IDA:MGI.
DR GO; GO:0060021; P:roof of mouth development; IMP:MGI.
DR GO; GO:0001967; P:suckling behavior; IMP:MGI.
DR GO; GO:0048485; P:sympathetic nervous system development; IDA:MGI.
DR GO; GO:0048538; P:thymus development; IMP:BHF-UCL.
DR GO; GO:0043586; P:tongue development; IMP:MGI.
DR GO; GO:0061032; P:visceral serous pericardium development; IMP:MGI.
DR Gene3D; 4.10.280.10; -; 1.
DR InterPro; IPR011598; bHLH_dom.
DR InterPro; IPR036638; HLH_DNA-bd_sf.
DR Pfam; PF00010; HLH; 1.
DR SMART; SM00353; HLH; 1.
DR SUPFAM; SSF47459; SSF47459; 1.
DR PROSITE; PS50888; BHLH; 1.
PE 1: Evidence at protein level;
KW Angiogenesis; Developmental protein; Differentiation; DNA-binding; Nucleus;
KW Reference proteome; Transcription; Transcription regulation.
FT CHAIN 1..217
FT /note="Heart- and neural crest derivatives-expressed
FT protein 2"
FT /id="PRO_0000127192"
FT DOMAIN 99..151
FT /note="bHLH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00981"
FT REGION 76..116
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT CONFLICT 92..93
FT /note="LG -> TA (in Ref. 3; AAA86274)"
FT /evidence="ECO:0000305"
FT CONFLICT 156
FT /note="A -> P (in Ref. 1; AAC52338)"
FT /evidence="ECO:0000305"
FT CONFLICT 166
FT /note="A -> G (in Ref. 3; AAA86274)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 217 AA; 23666 MW; 528F541BB2173F1E CRC64;
MSLVGGFPHH PVVHHEGYPF AAAAAAAAAA AASRCSHEEN PYFHGWLIGH PEMSPPDYSM
ALSYSPEYAS GAAGLDHSHY GGVPPGAGPP GLGGPRPVKR RGTANRKERR RTQSINSAFA
ELRECIPNVP ADTKLSKIKT LRLATSYIAY LMDLLAKDDQ NGEAEAFKAE IKKTDVKEEK
RKKELNEILK STVSSNDKKT KGRTGWPQHV WALELKQ
