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{{Infobox_gene}}
{{PBB_Controls
'''Heart- and neural crest derivatives-expressed protein 1''' is a [[protein]] that in humans is encoded by the ''HAND1'' [[gene]].<ref name="Russell_1998">{{cite journal | vauthors = Russell MW, Baker P, Izumo S | title = Cloning, chromosomal mapping, and expression of the human eHAND gene | journal = Mammalian Genome | volume = 8 | issue = 11 | pages = 863–5 | date = January 1998 | pmid = 9337404 | doi = 10.1007/s003359900596 }}</ref><ref name="Knöfler_1998">{{cite journal | vauthors = Knöfler M, Meinhardt G, Vasicek R, Husslein P, Egarter C | title = Molecular cloning of the human Hand1 gene/cDNA and its tissue-restricted expression in cytotrophoblastic cells and heart | journal = Gene | volume = 224 | issue = 1-2 | pages = 77–86 | date = December 1998 | pmid = 9931445 | pmc =  | doi = 10.1016/S0378-1119(98)00511-3 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: HAND1 heart and neural crest derivatives expressed 1 | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9421| accessdate = }}</ref>
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
A member of the HAND subclass of [[Basic helix-loop-helix|basic Helix-loop-helix (bHLH)]] transcription factors, the Heart and neural crest-derived transcript-1 (''HAND1)'' gene is vital for the development and differentiation of three distinct embryological lineages including the cardiac muscle cells of the heart, trophoblast of the placenta, and yolk sac vasculogenesis.<ref>{{cite journal | vauthors = Firulli AB | title = A HANDful of questions: the molecular biology of the heart and neural crest derivatives (HAND)-subclass of basic helix-loop-helix transcription factors | journal = Gene | volume = 312 | pages = 27–40 | date = July 2003 | pmid = 12909338 }}</ref><ref name="Smart_2010">{{cite journal | vauthors = Smart N, Dubé KN, Riley PR | title = Identification of Thymosin β4 as an effector of Hand1-mediated vascular development | journal = Nature Communications | volume = 1 | pages = 46 | date = July 2010 | pmid = 20975697 | doi = 10.1038/ncomms1041 }}</ref> Most highly related to [[Twist transcription factor|twist-like bHLH genes]] in amino acid identity and embryonic expression, HAND1 can form homo- and heterodimer combinations with multiple bHLH partners, mediating transcriptional activity in the nucleus.<ref name="Smart_2010" /><ref>{{cite journal | vauthors = Asuthkar S, Gogineni VR, Rao JS, Velpula KK | title = Nuclear translocation of Hand-1 acts as a molecular switch to regulate vascular radiosensitivity in medulloblastoma tumors: the protein uPAR is a cytoplasmic sequestration factor for Hand-1 | journal = Molecular Cancer Therapeutics | volume = 13 | issue = 5 | pages = 1309–22 | date = May 2014 | pmid = 24623737 | doi = 10.1158/1535-7163.MCT-13-0892 }}</ref>
{{GNF_Protein_box
| image = 
| image_source = 
| PDB =
| Name = Heart and neural crest derivatives expressed 1
| HGNCid = 4807
| Symbol = HAND1
| AltSymbols =; Hxt; Thing1; eHand
| OMIM = 602406
| ECnumber = 
| Homologene = 3545
| MGIid = 103577
| GeneAtlas_image1 = PBB_GE_HAND1_220138_at_tn.png
| Function = {{GNF_GO|id=GO:0003700 |text = transcription factor activity}} {{GNF_GO|id=GO:0008134 |text = transcription factor binding}} {{GNF_GO|id=GO:0016564 |text = transcription repressor activity}} {{GNF_GO|id=GO:0042803 |text = protein homodimerization activity}} {{GNF_GO|id=GO:0046982 |text = protein heterodimerization activity}}  
| Component = {{GNF_GO|id=GO:0005634 |text = nucleus}}
| Process = {{GNF_GO|id=GO:0000122 |text = negative regulation of transcription from RNA polymerase II promoter}} {{GNF_GO|id=GO:0001525 |text = angiogenesis}} {{GNF_GO|id=GO:0006355 |text = regulation of transcription, DNA-dependent}} {{GNF_GO|id=GO:0006366 |text = transcription from RNA polymerase II promoter}} {{GNF_GO|id=GO:0007275 |text = multicellular organismal development}} {{GNF_GO|id=GO:0007507 |text = heart development}} {{GNF_GO|id=GO:0030154 |text = cell differentiation}} {{GNF_GO|id=GO:0045944 |text = positive regulation of transcription from RNA polymerase II promoter}}  
  | Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 9421
    | Hs_Ensembl = ENSG00000113196
    | Hs_RefseqProtein = NP_004812
    | Hs_RefseqmRNA = NM_004821
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 5
    | Hs_GenLoc_start = 153834726
    | Hs_GenLoc_end = 153838017
    | Hs_Uniprot = O96004
    | Mm_EntrezGene = 15110
    | Mm_Ensembl = ENSMUSG00000037335
    | Mm_RefseqmRNA = NM_008213
    | Mm_RefseqProtein = NP_032239
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 11
    | Mm_GenLoc_start = 57644908
    | Mm_GenLoc_end = 57648342
    | Mm_Uniprot = Q5SQG0
  }}
}}
'''Heart and neural crest derivatives expressed 1''', also known as '''HAND1''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: HAND1 heart and neural crest derivatives expressed 1| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9421| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Function ==
{{PBB_Summary
| section_title =  
| summary_text = The protein encoded by this gene belongs to the basic helix-loop-helix family of transcription factors. This gene product is one of two closely related family members, the HAND proteins, which are asymmetrically expressed in the developing ventricular chambers and play an essential role in cardiac morphogenesis. Working in a complementary fashion, they function in the formation of the right ventricle and aortic arch arteries, implicating them as mediators of congenital heart disease. In addition, it has been suggested that this transcription factor may be required for early trophoblast differentiation.<ref name="entrez">{{cite web | title = Entrez Gene: HAND1 heart and neural crest derivatives expressed 1| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9421| accessdate = }}</ref>
}}


==References==
The protein encoded by this gene belongs to the basic helix-loop-helix family of transcription factors. This gene product is one of two closely related family members, the HAND proteins  are  expressed within the developing ventricular chambers, cardiac neural crest, endocardium (HAND2 only) and epicardium (HAND2 only) . HAND1 is expressed with myocardium of the primary heart field  and plays an essential but poorly understood role in cardiac morphogenesis.
{{reflist|2}}
 
==Further reading==
HAND1 works jointly with HAND2 in cardiac development of embryos based on a crucial HAND gene dosage system. If HAND1 is over or under expressed then morphological abnormalities can form; most notable are cleft lips and palates. Expression was modeled with a knock-in of phosphorylation to turn on and off gene expression which induced the craniofacial abnormalities.<ref name="Firulli_2014">{{cite journal | vauthors = Firulli BA, Fuchs RK, Vincentz JW, Clouthier DE, Firulli AB | title = Hand1 phosphoregulation within the distal arch neural crest is essential for craniofacial morphogenesis | journal = Development | volume = 141 | issue = 15 | pages = 3050–61 | date = August 2014 | pmid = 25053435 | pmc = 4197675 | doi = 10.1242/dev.107680 }}</ref> Knock-out experimentation on mice caused death and severe cardiac malformations such as failed cardiac looping, impaired ventricular development and defective chamber septation. This aids in the implication that HAND1 expression is a factor to patients suffering from congenital heart disease.<ref name="Reamon-Buettner_2009">{{cite journal | vauthors = Reamon-Buettner SM, Ciribilli Y, Traverso I, Kuhls B, Inga A, Borlak J | title = A functional genetic study identifies HAND1 mutations in septation defects of the human heart | journal = Human Molecular Genetics | volume = 18 | issue = 19 | pages = 3567–78 | date = October 2009 | pmid = 19586923 | doi = 10.1093/hmg/ddp305 }}</ref> However, a lack of HAND1 in the distal regions of the Neural Crest has no effect on cranial feature formation.<ref name="Firulli_2014" /> Mutation of HAND1 has been shown to hinder the effect of GATA4, another vital cardiac transcription factor, and is associated with congenital heart disease.<ref name = "Zhou_2016">{{cite journal | vauthors = Zhou YM, Dai XY, Qiu XB, Yuan F, Li RG, Xu YJ, Qu XK, Huang RT, Xue S, Yang YQ | title = HAND1 loss-of-function mutation associated with familial dilated cardiomyopathy | journal = Clinical Chemistry and Laboratory Medicine | volume = 54 | issue = 7 | pages = 1161–7 | date = July 2016 | pmid = 26581070 | doi = 10.1515/cclm-2015-0766 }}</ref> The lack of HAND1 detection in the developing embryo leads to many of the structural defects that causes heart disease and facial deformities while the dosage of HAND1 relates to the severity of these maladies.<ref name="Firulli_2014" />
{{refbegin | 2}}
 
{{PBB_Further_reading
HAND factors function in the formation of the right ventricle, left ventricle, aortic arch arteries, epicardium, and endocardium implicating them as mediators of congenital heart disease. In addition, HAND1 is uniquely expressed in trophoblasts and is essential for early trophoblast differentiation.<ref name="entrez" />
| citations =
 
*{{cite journal | author=Srivastava D |title=HAND proteins: molecular mediators of cardiac development and congenital heart disease. |journal=Trends Cardiovasc. Med. |volume=9 |issue= 1-2 |pages= 11-8 |year= 1999 |pmid= 10189962 |doi= }}
=== Cardiac morphogenesis ===
*{{cite journal  | author=Weber MC, de Clarke V, Harwin RM, Shiff CJ |title=An extended field trial of pyrimethamine combined with dapsone in the prophylaxis of malaria. |journal=The Central African journal of medicine |volume=21 |issue= 9 |pages= 187-92 |year= 1976 |pmid= 1182795 |doi= }}
 
*{{cite journal  | author=Cross SH, Charlton JA, Nan X, Bird AP |title=Purification of CpG islands using a methylated DNA binding column. |journal=Nat. Genet. |volume=6 |issue= 3 |pages= 236-44 |year= 1994 |pmid= 8012384 |doi= 10.1038/ng0394-236 }}
In the third week of fetal development the rudimentary heart (bilaterally symmetrical cardiac tube) undergoes a characteristic dextral looping, forming an asymmetrical structure with bulges that represent the incipient ventricular and atrial chambers of the heart.<ref name="Carlson_2014">{{cite book | last1 = Carlson | first1 = Bruce M. | name-list-format = vanc | title = Human Embryology and Developmental Biology | date=2014 | publisher = Elsevier/Saunders | location = Philadelphia, Pa. | isbn = 978-1-4557-2797-1 | edition = 5th }}</ref>  Arising from cells derived from the primary heart field in the cardiac crescent, ''HAND1'' goes from being expressed on both sides of the heart tube to the ventral surface of the caudal heart segment and the aortic sac, then being restricted to the outer curvature of the left ventricle in the looped heart.<ref name="Carlson_2014" /><ref>{{cite journal | vauthors = Harvey RP | title = Seeking a regulatory roadmap for heart morphogenesis | journal = Seminars in Cell & Developmental Biology | volume = 10 | issue = 1 | pages = 99–107 | date = February 1999 | pmid = 10355034 | doi = 10.1006/scdb.1998.0277 }}</ref><ref>{{cite journal | vauthors = Togi K, Kawamoto T, Yamauchi R, Yoshida Y, Kita T, Tanaka M | title = Role of Hand1/eHAND in the dorso-ventral patterning and interventricular septum formation in the embryonic heart | journal = Molecular and Cellular Biology | volume = 24 | issue = 11 | pages = 4627–35 | date = June 2004 | pmid = 15143159 | doi = 10.1128/MCB.24.11.4627-4635.2004 }}</ref> In conjunction with ''[[HAND2]]'' (a fellow bHLH transcription factor), complementary and overlapping expression patterns are thought to play a role in interpreting asymmetrical signals in the developing heart which leads to the characteristic looping.<ref name="Carlson_2014" /><ref name="McFadden_2005">{{cite journal | vauthors = McFadden DG, Barbosa AC, Richardson JA, Schneider MD, Srivastava D, Olson EN | title = The Hand1 and Hand2 transcription factors regulate expansion of the embryonic cardiac ventricles in a gene dosage-dependent manner | journal = Development | volume = 132 | issue = 1 | pages = 189–201 | date = January 2005 | pmid = 15576406 | doi = 10.1242/dev.01562 }}</ref>    The two are implemented in cardiac development of embryos based on a crucial HAND gene dosage system. If ''HAND1'' is over or under expressed then morphological abnormalities can form; most notable are cleft lips and palates. Expression was modeled with a knock-in of phosphorylation to turn on and off gene expression which induced the craniofacial abnormalities.<ref name="Firulli_2014"/>
*{{cite journal  | author=Russell MW, Baker P, Izumo S |title=Cloning, chromosomal mapping, and expression of the human eHAND gene. |journal=Mamm. Genome |volume=8 |issue= 11 |pages= 863-5 |year= 1998 |pmid= 9337404 |doi}}
 
*{{cite journal  | author=Knöfler M, Meinhardt G, Vasicek R, ''et al.'' |title=Molecular cloning of the human Hand1 gene/cDNA and its tissue-restricted expression in cytotrophoblastic cells and heart. |journal=Gene |volume=224 |issue= 1-2 |pages= 77-86 |year= 1999 |pmid= 9931445 |doi= }}
''HAND1'' mutants also appear to develop a spectrum of cardiac abnormalities, as demonstrated in knock-out experimentation in the mouse model, where ''HAND1''-null mice displayed defects in the ventral septum, malformation of the AV valve, hypoplastic ventricles, and outflow tract abnormalities.<ref name="McFadden_2005" /><ref>{{cite journal | vauthors = Wolf M, Basson CT | title = The molecular genetics of congenital heart disease: a review of recent developments | journal = Current Opinion in Cardiology | volume = 25 | issue = 3 | pages = 192–7 | date = May 2010 | pmid = 20186050 | doi = 10.1097/HCO.0b013e328337b4ce }}</ref> In humans, evidence of a frameshift mutation in the bHLH domain of ''HAND1'' has been correlated with hypoplastic left heart syndrome (a serious form of [[Congenital heart defect|congenital heart disease]] where the left side of the heart is severely underdeveloped), aiding in the implication that ''HAND1'' expression is a factor to patients suffering from the disease.<ref name="Reamon-Buettner_2009" /><ref>{{cite journal | vauthors = Reamon-Buettner SM, Ciribilli Y, Inga A, Borlak J | title = A loss-of-function mutation in the binding domain of HAND1 predicts hypoplasia of the human hearts | journal = Human Molecular Genetics | volume = 17 | issue = 10 | pages = 1397–405 | date = May 2008 | pmid = 18276607 | doi = 10.1093/hmg/ddn027 }}</ref>
*{{cite journal  | author=Scott IC, Anson-Cartwright L, Riley P, ''et al.'' |title=The HAND1 basic helix-loop-helix transcription factor regulates trophoblast differentiation via multiple mechanisms. |journal=Mol. Cell. Biol. |volume=20 |issue= 2 |pages= 530-41 |year= 2000 |pmid= 10611232 |doi= }}
 
*{{cite journal | author=Bounpheng MA, Morrish TA, Dodds SG, Christy BA |title=Negative regulation of selected bHLH proteins by eHAND. |journal=Exp. Cell Res. |volume=257 |issue= 2 |pages= 320-31 |year= 2000 |pmid= 10837146 |doi= 10.1006/excr.2000.4898 }}
However, a lack of ''HAND1'' in the distal regions of the Neural Crest has no effect on cranial feature formation.<ref name="Firulli_2014" /> Mutation of ''HAND1'' has been shown to hinder the effect of GATA4, another vital cardiac transcription factor, and is associated with congenital heart disease.<ref name = "Zhou_2016" /> The lack of ''HAND1'' detection in the developing embryo leads to many of the structural defects that causes heart disease and facial deformities while the dosage of ''HAND1'' relates to the severity of these maladies.<ref name="Firulli_2014" />
*{{cite journal | author=Firulli BA, Hadzic DB, McDaid JR, Firulli AB |title=The basic helix-loop-helix transcription factors dHAND and eHAND exhibit dimerization characteristics that suggest complex regulation of function. |journal=J. Biol. Chem. |volume=275 |issue= 43 |pages= 33567-73 |year= 2000 |pmid= 10924525 |doi= 10.1074/jbc.M005888200 }}
 
*{{cite journal  | author=Knöfler M, Meinhardt G, Bauer S, ''et al.'' |title=Human Hand1 basic helix-loop-helix (bHLH) protein: extra-embryonic expression pattern, interaction partners and identification of its transcriptional repressor domains. |journal=Biochem. J. |volume=361 |issue= Pt 3 |pages= 641-51 |year= 2002 |pmid= 11802795 |doi=  }}
=== Trophoblast differentiation ===
*{{cite journal | author=Dai YS, Cserjesi P |title=The basic helix-loop-helix factor, HAND2, functions as a transcriptional activator by binding to E-boxes as a heterodimer. |journal=J. Biol. Chem. |volume=277 |issue= 15 |pages= 12604-12 |year= 2002 |pmid= 11812799 |doi= 10.1074/jbc.M200283200 }}
 
*{{cite journal | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
In addition, ''HAND1'' is uniquely expressed in [[trophoblast]]s and is essential for early trophoblast giant cell differentiation.<ref name="Scott_2000">{{cite journal | vauthors = Scott IC, Anson-Cartwright L, Riley P, Reda D, Cross JC | title = The HAND1 basic helix-loop-helix transcription factor regulates trophoblast differentiation via multiple mechanisms | journal = Molecular and Cellular Biology | volume = 20 | issue = 2 | pages = 530–41 | date = January 2000 | pmid = 10611232 | pmc = 85124 | doi = 10.1128/MCB.20.2.530-541.2000 }}</ref> Trophoblast giant cells are necessary in order for placental development to proceed, participating in vital processes such as blastocyst implantation, remodeling of the maternal decidua, and secretion of hormones.<ref name="Scott_2000" />  The importance of this relationship is demonstrated in ''HAND1''-null mutant mice, which display significant abnormalities in trophoblast development, such as a reduced ectoplacental cone, thin parietal yolk sac, and reduced density of trophoblast giant cells.<ref name="Riley_1998">{{cite journal | vauthors = Riley P, Anson-Cartwright L, Cross JC | title = The Hand1 bHLH transcription factor is essential for placentation and cardiac morphogenesis | journal = Nature Genetics | volume = 18 | issue = 3 | pages = 271–5 | date = March 1998 | pmid = 9500551 | doi = 10.1038/ng0398-271 }}]</ref> These homozygous ''HAND1''-null mutant embryos were arrested by E7.5 of gestation, though could be saved by contribution of wild-type cells to the trophoblast.<ref name="Riley_1998" />
*{{cite journal  | author=Srivastava D, Gottlieb PD, Olson EN |title=Molecular mechanisms of ventricular hypoplasia. |journal=Cold Spring Harb. Symp. Quant. Biol. |volume=67 |issue= |pages= 121-5 |year= 2003 |pmid= 12858532 |doi= }}
 
*{{cite journal  | author=Firulli BA, Howard MJ, McDaid JR, ''et al.'' |title=PKA, PKC, and the protein phosphatase 2A influence HAND factor function: a mechanism for tissue-specific transcriptional regulation. |journal=Mol. Cell |volume=12 |issue= 5 |pages= 1225-37 |year= 2004 |pmid= 14636580 |doi= }}
=== Yolk sac vasculogenesis ===
*{{cite journal | author=Gerhard DS, Wagner L, Feingold EA, ''et al.'' |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121-7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 }}
 
*{{cite journal | author=Hill AA, Riley PR |title=Differential regulation of Hand1 homodimer and Hand1-E12 heterodimer activity by the cofactor FHL2. |journal=Mol. Cell. Biol. |volume=24 |issue= 22 |pages= 9835-47 |year= 2004 |pmid= 15509787 |doi= 10.1128/MCB.24.22.9835-9847.2004 }}
Expressed in high levels in the extraembryonic membranes throughout development, ''HAND1'' also plays a functional role in vascular development of the yolk sac.<ref name="Morikawa_2004">{{cite journal | vauthors = Morikawa Y, Cserjesi P | title = Extra-embryonic vasculature development is regulated by the transcription factor HAND1 | journal = Development | volume = 131 | issue = 9 | pages = 2195–204 | date = May 2004 | pmid = 15073150 | doi = 10.1242/dev.01091 }}</ref>  Though not strictly required for vasculogenesis, data has shown that ''HAND1'' contributes to the fine-tuning of the vasculogenic response in the yolk sac, recruiting smooth muscle cells to the endothelial network in order to refine the primitive endothelial plexus to a functional vascular system.<ref name="Morikawa_2004" /><ref name="Smart_2010" />  This relationship has been demonstrated in the ''HAND1''-null mouse model, where embryos lacking the ''HAND1'' gene had a yolk sac vasculature defect caused by lack of vasculature refinement leading to the accumulation of [[Haematopoiesis|hematopoietic]] cells between the yolk sac and the amnion.<ref name="Morikawa_2004" />
*{{cite journal | author=Morin S, Pozzulo G, Robitaille L, ''et al.'' |title=MEF2-dependent recruitment of the HAND1 transcription factor results in synergistic activation of target promoters. |journal=J. Biol. Chem. |volume=280 |issue= 37 |pages= 32272-8 |year= 2005 |pmid= 16043483 |doi= 10.1074/jbc.M507640200 }}
 
}}
== References ==
{{reflist|33em}}
 
== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Srivastava D | title = HAND proteins: molecular mediators of cardiac development and congenital heart disease | journal = Trends in Cardiovascular Medicine | volume = 9 | issue = 1-2 | pages = 11–8 | year = 1999 | pmid = 10189962 | doi = 10.1016/S1050-1738(98)00033-4 }}
* {{cite journal | vauthors = Weber MC, de Clarke V, Harwin RM, Shiff CJ | title = An extended field trial of pyrimethamine combined with dapsone in the prophylaxis of malaria | journal = The Central African Journal of Medicine | volume = 21 | issue = 9 | pages = 187–92 | date = September 1975 | pmid = 1182795 | doi =  }}
* {{cite journal | vauthors = Cross SH, Charlton JA, Nan X, Bird AP | title = Purification of CpG islands using a methylated DNA binding column | journal = Nature Genetics | volume = 6 | issue = 3 | pages = 236–44 | date = March 1994 | pmid = 8012384 | doi = 10.1038/ng0394-236 }}
* {{cite journal | vauthors = Bounpheng MA, Morrish TA, Dodds SG, Christy BA | title = Negative regulation of selected bHLH proteins by eHAND | journal = Experimental Cell Research | volume = 257 | issue = 2 | pages = 320–31 | date = June 2000 | pmid = 10837146 | doi = 10.1006/excr.2000.4898 }}
* {{cite journal | vauthors = Firulli BA, Hadzic DB, McDaid JR, Firulli AB | title = The basic helix-loop-helix transcription factors dHAND and eHAND exhibit dimerization characteristics that suggest complex regulation of function | journal = The Journal of Biological Chemistry | volume = 275 | issue = 43 | pages = 33567–73 | date = October 2000 | pmid = 10924525 | pmc = 2561327 | doi = 10.1074/jbc.M005888200 }}
* {{cite journal | vauthors = Knöfler M, Meinhardt G, Bauer S, Loregger T, Vasicek R, Bloor DJ, Kimber SJ, Husslein P | title = Human Hand1 basic helix-loop-helix (bHLH) protein: extra-embryonic expression pattern, interaction partners and identification of its transcriptional repressor domains | journal = The Biochemical Journal | volume = 361 | issue = Pt 3 | pages = 641–51 | date = February 2002 | pmid = 11802795 | pmc = 1222348 | doi = 10.1042/0264-6021:3610641 }}
* {{cite journal | vauthors = Dai YS, Cserjesi P | title = The basic helix-loop-helix factor, HAND2, functions as a transcriptional activator by binding to E-boxes as a heterodimer | journal = The Journal of Biological Chemistry | volume = 277 | issue = 15 | pages = 12604–12 | date = April 2002 | pmid = 11812799 | doi = 10.1074/jbc.M200283200 }}
* {{cite journal | vauthors = Srivastava D, Gottlieb PD, Olson EN | title = Molecular mechanisms of ventricular hypoplasia | journal = Cold Spring Harbor Symposia on Quantitative Biology | volume = 67 | issue =  | pages = 121–5 | year = 2003 | pmid = 12858532 | doi = 10.1101/sqb.2002.67.121 }}
* {{cite journal | vauthors = Firulli BA, Howard MJ, McDaid JR, McIlreavey L, Dionne KM, Centonze VE, Cserjesi P, Virshup DM, Firulli AB | title = PKA, PKC, and the protein phosphatase 2A influence HAND factor function: a mechanism for tissue-specific transcriptional regulation | journal = Molecular Cell | volume = 12 | issue = 5 | pages = 1225–37 | date = November 2003 | pmid = 14636580 | doi = 10.1016/S1097-2765(03)00425-8 }}
* {{cite journal | vauthors = Hill AA, Riley PR | title = Differential regulation of Hand1 homodimer and Hand1-E12 heterodimer activity by the cofactor FHL2 | journal = Molecular and Cellular Biology | volume = 24 | issue = 22 | pages = 9835–47 | date = November 2004 | pmid = 15509787 | pmc = 525463 | doi = 10.1128/MCB.24.22.9835-9847.2004 }}
* {{cite journal | vauthors = Morin S, Pozzulo G, Robitaille L, Cross J, Nemer M | title = MEF2-dependent recruitment of the HAND1 transcription factor results in synergistic activation of target promoters | journal = The Journal of Biological Chemistry | volume = 280 | issue = 37 | pages = 32272–8 | date = September 2005 | pmid = 16043483 | doi = 10.1074/jbc.M507640200 }}
{{refend}}
{{refend}}


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Revision as of 13:27, 31 August 2017

VALUE_ERROR (nil)
Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

n/a

n/a

RefSeq (protein)

n/a

n/a

Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human

Heart- and neural crest derivatives-expressed protein 1 is a protein that in humans is encoded by the HAND1 gene.[1][2][3]

A member of the HAND subclass of basic Helix-loop-helix (bHLH) transcription factors, the Heart and neural crest-derived transcript-1 (HAND1) gene is vital for the development and differentiation of three distinct embryological lineages including the cardiac muscle cells of the heart, trophoblast of the placenta, and yolk sac vasculogenesis.[4][5] Most highly related to twist-like bHLH genes in amino acid identity and embryonic expression, HAND1 can form homo- and heterodimer combinations with multiple bHLH partners, mediating transcriptional activity in the nucleus.[5][6]

Function

The protein encoded by this gene belongs to the basic helix-loop-helix family of transcription factors. This gene product is one of two closely related family members, the HAND proteins are expressed within the developing ventricular chambers, cardiac neural crest, endocardium (HAND2 only) and epicardium (HAND2 only) . HAND1 is expressed with myocardium of the primary heart field and plays an essential but poorly understood role in cardiac morphogenesis.

HAND1 works jointly with HAND2 in cardiac development of embryos based on a crucial HAND gene dosage system. If HAND1 is over or under expressed then morphological abnormalities can form; most notable are cleft lips and palates. Expression was modeled with a knock-in of phosphorylation to turn on and off gene expression which induced the craniofacial abnormalities.[7] Knock-out experimentation on mice caused death and severe cardiac malformations such as failed cardiac looping, impaired ventricular development and defective chamber septation. This aids in the implication that HAND1 expression is a factor to patients suffering from congenital heart disease.[8] However, a lack of HAND1 in the distal regions of the Neural Crest has no effect on cranial feature formation.[7] Mutation of HAND1 has been shown to hinder the effect of GATA4, another vital cardiac transcription factor, and is associated with congenital heart disease.[9] The lack of HAND1 detection in the developing embryo leads to many of the structural defects that causes heart disease and facial deformities while the dosage of HAND1 relates to the severity of these maladies.[7]

HAND factors function in the formation of the right ventricle, left ventricle, aortic arch arteries, epicardium, and endocardium implicating them as mediators of congenital heart disease. In addition, HAND1 is uniquely expressed in trophoblasts and is essential for early trophoblast differentiation.[3]

Cardiac morphogenesis

In the third week of fetal development the rudimentary heart (bilaterally symmetrical cardiac tube) undergoes a characteristic dextral looping, forming an asymmetrical structure with bulges that represent the incipient ventricular and atrial chambers of the heart.[10] Arising from cells derived from the primary heart field in the cardiac crescent, HAND1 goes from being expressed on both sides of the heart tube to the ventral surface of the caudal heart segment and the aortic sac, then being restricted to the outer curvature of the left ventricle in the looped heart.[10][11][12] In conjunction with HAND2 (a fellow bHLH transcription factor), complementary and overlapping expression patterns are thought to play a role in interpreting asymmetrical signals in the developing heart which leads to the characteristic looping.[10][13] The two are implemented in cardiac development of embryos based on a crucial HAND gene dosage system. If HAND1 is over or under expressed then morphological abnormalities can form; most notable are cleft lips and palates. Expression was modeled with a knock-in of phosphorylation to turn on and off gene expression which induced the craniofacial abnormalities.[7]

HAND1 mutants also appear to develop a spectrum of cardiac abnormalities, as demonstrated in knock-out experimentation in the mouse model, where HAND1-null mice displayed defects in the ventral septum, malformation of the AV valve, hypoplastic ventricles, and outflow tract abnormalities.[13][14] In humans, evidence of a frameshift mutation in the bHLH domain of HAND1 has been correlated with hypoplastic left heart syndrome (a serious form of congenital heart disease where the left side of the heart is severely underdeveloped), aiding in the implication that HAND1 expression is a factor to patients suffering from the disease.[8][15]

However, a lack of HAND1 in the distal regions of the Neural Crest has no effect on cranial feature formation.[7] Mutation of HAND1 has been shown to hinder the effect of GATA4, another vital cardiac transcription factor, and is associated with congenital heart disease.[9] The lack of HAND1 detection in the developing embryo leads to many of the structural defects that causes heart disease and facial deformities while the dosage of HAND1 relates to the severity of these maladies.[7]

Trophoblast differentiation

In addition, HAND1 is uniquely expressed in trophoblasts and is essential for early trophoblast giant cell differentiation.[16] Trophoblast giant cells are necessary in order for placental development to proceed, participating in vital processes such as blastocyst implantation, remodeling of the maternal decidua, and secretion of hormones.[16] The importance of this relationship is demonstrated in HAND1-null mutant mice, which display significant abnormalities in trophoblast development, such as a reduced ectoplacental cone, thin parietal yolk sac, and reduced density of trophoblast giant cells.[17] These homozygous HAND1-null mutant embryos were arrested by E7.5 of gestation, though could be saved by contribution of wild-type cells to the trophoblast.[17]

Yolk sac vasculogenesis

Expressed in high levels in the extraembryonic membranes throughout development, HAND1 also plays a functional role in vascular development of the yolk sac.[18] Though not strictly required for vasculogenesis, data has shown that HAND1 contributes to the fine-tuning of the vasculogenic response in the yolk sac, recruiting smooth muscle cells to the endothelial network in order to refine the primitive endothelial plexus to a functional vascular system.[18][5] This relationship has been demonstrated in the HAND1-null mouse model, where embryos lacking the HAND1 gene had a yolk sac vasculature defect caused by lack of vasculature refinement leading to the accumulation of hematopoietic cells between the yolk sac and the amnion.[18]

References

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  2. Knöfler M, Meinhardt G, Vasicek R, Husslein P, Egarter C (December 1998). "Molecular cloning of the human Hand1 gene/cDNA and its tissue-restricted expression in cytotrophoblastic cells and heart". Gene. 224 (1–2): 77–86. doi:10.1016/S0378-1119(98)00511-3. PMID 9931445.
  3. 3.0 3.1 "Entrez Gene: HAND1 heart and neural crest derivatives expressed 1".
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  6. Asuthkar S, Gogineni VR, Rao JS, Velpula KK (May 2014). "Nuclear translocation of Hand-1 acts as a molecular switch to regulate vascular radiosensitivity in medulloblastoma tumors: the protein uPAR is a cytoplasmic sequestration factor for Hand-1". Molecular Cancer Therapeutics. 13 (5): 1309–22. doi:10.1158/1535-7163.MCT-13-0892. PMID 24623737.
  7. 7.0 7.1 7.2 7.3 7.4 7.5 Firulli BA, Fuchs RK, Vincentz JW, Clouthier DE, Firulli AB (August 2014). "Hand1 phosphoregulation within the distal arch neural crest is essential for craniofacial morphogenesis". Development. 141 (15): 3050–61. doi:10.1242/dev.107680. PMC 4197675. PMID 25053435.
  8. 8.0 8.1 Reamon-Buettner SM, Ciribilli Y, Traverso I, Kuhls B, Inga A, Borlak J (October 2009). "A functional genetic study identifies HAND1 mutations in septation defects of the human heart". Human Molecular Genetics. 18 (19): 3567–78. doi:10.1093/hmg/ddp305. PMID 19586923.
  9. 9.0 9.1 Zhou YM, Dai XY, Qiu XB, Yuan F, Li RG, Xu YJ, Qu XK, Huang RT, Xue S, Yang YQ (July 2016). "HAND1 loss-of-function mutation associated with familial dilated cardiomyopathy". Clinical Chemistry and Laboratory Medicine. 54 (7): 1161–7. doi:10.1515/cclm-2015-0766. PMID 26581070.
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This article incorporates text from the United States National Library of Medicine, which is in the public domain.