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   24-JAN-2024, entry version 200.
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; 10090-ENSMUSP00000044983; -.
DR   ProteomicsDB; 271390; -.
DR   Antibodypedia; 28534; 313 antibodies from 30 providers.
DR   DNASU; 15111; -.
DR   Ensembl; ENSMUST00000040104.5; ENSMUSP00000044983.4; ENSMUSG00000038193.5.
DR   GeneID; 15111; -.
DR   KEGG; mmu:15111; -.
DR   UCSC; uc009lss.2; mouse.
DR   AGR; MGI:103580; -.
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; 5386175at2759; -.
DR   PhylomeDB; Q61039; -.
DR   TreeFam; TF315153; -.
DR   BioGRID-ORCS; 15111; 2 hits in 78 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 163 other cell types or tissues.
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: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: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:0042421; P:norepinephrine biosynthetic process; IMP:BHF-UCL.
DR   GO; GO:0042475; P:odontogenesis of dentin-containing tooth; IGI:MGI.
DR   GO; GO:0001649; P:osteoblast differentiation; IMP:MGI.
DR   GO; GO:0003151; P:outflow tract morphogenesis; IMP:BHF-UCL.
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:0045893; P:positive regulation of DNA-templated transcription; IDA: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:2001262; P:positive regulation of semaphorin-plexin signaling pathway; IMP:BHF-UCL.
DR   GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:BHF-UCL.
DR   GO; GO:1903929; P:primary palate development; IMP:MGI.
DR   GO; GO:0006355; P:regulation of DNA-templated transcription; IDA: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: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   CDD; cd11471; bHLH_TS_HAND2; 1.
DR   Gene3D; 4.10.280.10; Helix-loop-helix DNA-binding domain; 1.
DR   InterPro; IPR011598; bHLH_dom.
DR   InterPro; IPR036638; HLH_DNA-bd_sf.
DR   PANTHER; PTHR23349; BASIC HELIX-LOOP-HELIX TRANSCRIPTION FACTOR, TWIST; 1.
DR   PANTHER; PTHR23349:SF41; HEART- AND NEURAL CREST DERIVATIVES-EXPRESSED PROTEIN 2; 1.
DR   Pfam; PF00010; HLH; 1.
DR   SMART; SM00353; HLH; 1.
DR   SUPFAM; SSF47459; HLH, helix-loop-helix DNA-binding domain; 1.
DR   PROSITE; PS50888; BHLH; 1.
DR   Genevisible; Q61039; MM.
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
//