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HAND1
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<h2 id="function">Function</h2> <p>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. </p><p>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.<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> 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 with congenital heart disease.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> However, a lack of HAND1 in the distal regions of the Neural Crest has no effect on cranial feature formation.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> Mutation of HAND1 has been shown to hinder the effect of GATA4, another vital cardiac transcription factor, and is associated with congenital heart disease.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> 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.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> </p><p>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.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> </p> <h3>Cardiac morphogenesis</h3> <p>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.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> Arising from cells derived from the primary heart field in the cardiac crescent, <i>HAND1</i> 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.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a><a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a><a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> In conjunction with <i><a href="/facts/HAND2/8XMEYwr5">HAND2</a></i> (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.<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a><a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a> The two are implemented in cardiac development of embryos based on a crucial HAND gene dosage system. If <i>HAND1</i> 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.<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> </p><p><i>HAND1</i> mutants also appear to develop a spectrum of cardiac abnormalities, as demonstrated in knock-out experimentation in the mouse model, where <i>HAND1</i>-null mice displayed defects in the ventral septum, malformation of the AV valve, hypoplastic ventricles, and outflow tract abnormalities.<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a><a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a> In humans, evidence of a frameshift mutation in the bHLH domain of <i>HAND1</i> has been correlated with hypoplastic left heart syndrome (a serious form of <a href="/facts/Congenital_heart_defect/QsuPPC2Y">congenital heart disease</a> where the left side of the heart is severely underdeveloped), aiding in the implication that <i>HAND1</i> expression is a factor to patients with the disease.<a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a><a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a> </p><p>However, a lack of <i>HAND1</i> in the distal regions of the Neural Crest has no effect on cranial feature formation.<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a> Mutation of <i>HAND1</i> has been shown to hinder the effect of GATA4, another vital cardiac transcription factor, and is associated with congenital heart disease.<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a> The lack of <i>HAND1</i> detection in the developing embryo leads to many of the structural defects that causes heart disease and facial deformities while the dosage of <i>HAND1</i> relates to the severity of these maladies.<a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a> </p> <h3>Trophoblast differentiation</h3> <p>In addition, <i>HAND1</i> is uniquely expressed in <a href="/facts/Trophoblast/dzVMtog3">trophoblasts</a> and is essential for early trophoblast giant cell differentiation.<a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a> 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.<a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a> The importance of this relationship is demonstrated in <i>HAND1</i>-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.<a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a> These homozygous <i>HAND1</i>-null mutant embryos were arrested by E7.5 of gestation, though could be saved by contribution of wild-type cells to the trophoblast.<a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a> </p> <h3>Yolk sac vasculogenesis</h3> <p>Expressed in high levels in the extraembryonic membranes throughout development, <i>HAND1</i> also plays a functional role in vascular development of the yolk sac.<a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a> Though not strictly required for vasculogenesis, data has shown that <i>HAND1</i> 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.<a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a><a class="footnote-ref" id="fnref:34" href="#fn:34"><sup>34</sup></a> This relationship has been demonstrated in the <i>HAND1</i>-null mouse model, where embryos lacking the <i>HAND1</i> gene had a yolk sac vasculature defect caused by lack of vasculature refinement leading to the accumulation of <a href="/facts/Haematopoiesis/VRDwMymd">hematopoietic</a> cells between the yolk sac and the amnion.<a class="footnote-ref" id="fnref:35" href="#fn:35"><sup>35</sup></a> </p> <h2 id="further-reading">Further reading</h2> <ul><li>Srivastava D (1999). "HAND proteins: molecular mediators of cardiac development and congenital heart disease". <i>Trends in Cardiovascular Medicine</i>. 9 (1–2): 11–8. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2FS1050-1738%2898%2900033-4">10.1016/S1050-1738(98)00033-4</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/10189962">10189962</a>.</li> <li>Weber MC, de Clarke V, Harwin RM, Shiff CJ (September 1975). "An extended field trial of pyrimethamine combined with dapsone in the prophylaxis of malaria". <i>The Central African Journal of Medicine</i>. 21 (9): 187–92. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/1182795">1182795</a>.</li> <li>Cross SH, Charlton JA, Nan X, Bird AP (March 1994). "Purification of CpG islands using a methylated DNA binding column". <i>Nature Genetics</i>. 6 (3): 236–44. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1038%2Fng0394-236">10.1038/ng0394-236</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/8012384">8012384</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:12847618">12847618</a>.</li> <li>Bounpheng MA, Morrish TA, Dodds SG, Christy BA (June 2000). "Negative regulation of selected bHLH proteins by eHAND". <i>Experimental Cell Research</i>. 257 (2): 320–31. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1006%2Fexcr.2000.4898">10.1006/excr.2000.4898</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/10837146">10837146</a>.</li> <li>Firulli BA, Hadzic DB, McDaid JR, Firulli AB (October 2000). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2561327">"The basic helix-loop-helix transcription factors dHAND and eHAND exhibit dimerization characteristics that suggest complex regulation of function"</a>. <i>The Journal of Biological Chemistry</i>. 275 (43): 33567–73. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1074%2Fjbc.M005888200">10.1074/jbc.M005888200</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2561327">2561327</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/10924525">10924525</a>.</li> <li>Knöfler M, Meinhardt G, Bauer S, Loregger T, Vasicek R, Bloor DJ, Kimber SJ, Husslein P (February 2002). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1222348">"Human Hand1 basic helix-loop-helix (bHLH) protein: extra-embryonic expression pattern, interaction partners and identification of its transcriptional repressor domains"</a>. <i>The Biochemical Journal</i>. 361 (Pt 3): 641–51. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1042%2F0264-6021%3A3610641">10.1042/0264-6021:3610641</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1222348">1222348</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/11802795">11802795</a>.</li> <li>Dai YS, Cserjesi P (April 2002). <a href="https://doi.org/10.1074%2Fjbc.M200283200">"The basic helix-loop-helix factor, HAND2, functions as a transcriptional activator by binding to E-boxes as a heterodimer"</a>. <i>The Journal of Biological Chemistry</i>. 277 (15): 12604–12. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1074%2Fjbc.M200283200">10.1074/jbc.M200283200</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/11812799">11812799</a>.</li> <li>Srivastava D, Gottlieb PD, Olson EN (2003). "Molecular mechanisms of ventricular hypoplasia". <i>Cold Spring Harbor Symposia on Quantitative Biology</i>. 67: 121–5. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1101%2Fsqb.2002.67.121">10.1101/sqb.2002.67.121</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/12858532">12858532</a>.</li> <li>Firulli BA, Howard MJ, McDaid JR, McIlreavey L, Dionne KM, Centonze VE, Cserjesi P, Virshup DM, Firulli AB (November 2003). <a href="https://doi.org/10.1016%2FS1097-2765%2803%2900425-8">"PKA, PKC, and the protein phosphatase 2A influence HAND factor function: a mechanism for tissue-specific transcriptional regulation"</a>. <i>Molecular Cell</i>. 12 (5): 1225–37. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2FS1097-2765%2803%2900425-8">10.1016/S1097-2765(03)00425-8</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/14636580">14636580</a>.</li> <li>Hill AA, Riley PR (November 2004). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC525463">"Differential regulation of Hand1 homodimer and Hand1-E12 heterodimer activity by the cofactor FHL2"</a>. <i>Molecular and Cellular Biology</i>. 24 (22): 9835–47. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1128%2FMCB.24.22.9835-9847.2004">10.1128/MCB.24.22.9835-9847.2004</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC525463">525463</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/15509787">15509787</a>.</li> <li>Morin S, Pozzulo G, Robitaille L, Cross J, Nemer M (September 2005). <a href="https://doi.org/10.1074%2Fjbc.M507640200">"MEF2-dependent recruitment of the HAND1 transcription factor results in synergistic activation of target promoters"</a>. <i>The Journal of Biological Chemistry</i>. 280 (37): 32272–8. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1074%2Fjbc.M507640200">10.1074/jbc.M507640200</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/16043483">16043483</a>.</li></ul> <h2 id="external-links">External links</h2> <ul><li><a href="https://meshb.nlm.nih.gov/record/ui?name=HAND1+protein%2C+human">HAND1+protein,+human</a> at the U.S. National Library of Medicine <a href="/facts/Medical_Subject_Headings/C57g2JuF">Medical Subject Headings</a> (MeSH)</li></ul> <p><i>This article incorporates text from the <a href="/facts/United_States_National_Library_of_Medicine/Hzty0MCX">United States National Library of Medicine</a>, which is in the <a href="/facts/Public_domain/YWKMDKw4">public domain</a>.</i> </p> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Russell MW, Baker P, Izumo S (January 1998). "Cloning, chromosomal mapping, and expression of the human eHAND gene". Mammalian Genome. 8 (11): 863–5. doi:10.1007/s003359900596. hdl:2027.42/42138. PMID 9337404. S2CID 7799338. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>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. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>"Entrez Gene: HAND1 heart and neural crest derivatives expressed 1". <a href="https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9421" target="_blank">https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9421</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>Firulli AB (July 2003). "A HANDful of questions: the molecular biology of the heart and neural crest derivatives (HAND)-subclass of basic helix-loop-helix transcription factors". Gene. 312: 27–40. doi:10.1016/s0378-1119(03)00669-3. PMID 12909338. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>Smart N, Dubé KN, Riley PR (July 2010). "Identification of Thymosin β4 as an effector of Hand1-mediated vascular development". Nature Communications. 1 (4): 46. Bibcode:2010NatCo...1...46S. doi:10.1038/ncomms1041. PMC 2963826. PMID 20975697. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2963826" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2963826</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Smart N, Dubé KN, Riley PR (July 2010). "Identification of Thymosin β4 as an effector of Hand1-mediated vascular development". Nature Communications. 1 (4): 46. Bibcode:2010NatCo...1...46S. doi:10.1038/ncomms1041. PMC 2963826. PMID 20975697. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2963826" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2963826</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>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. <a href="https://doi.org/10.1158%2F1535-7163.MCT-13-0892" target="_blank">https://doi.org/10.1158%2F1535-7163.MCT-13-0892</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>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. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4197675" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4197675</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>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. <a href="https://doi.org/10.1093%2Fhmg%2Fddp305" target="_blank">https://doi.org/10.1093%2Fhmg%2Fddp305</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li> <li id="fn:10"><p>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. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4197675" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4197675</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></p></li> <li id="fn:11"><p>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. S2CID 22700829. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:11" class="footnote-back-ref">↩</a></p></li> <li id="fn:12"><p>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. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4197675" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4197675</a> <a href="#fnref:12" class="footnote-back-ref">↩</a></p></li> <li id="fn:13"><p>"Entrez Gene: HAND1 heart and neural crest derivatives expressed 1". <a href="https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9421" target="_blank">https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9421</a> <a href="#fnref:13" class="footnote-back-ref">↩</a></p></li> <li id="fn:14"><p>Carlson BM (2014). Human Embryology and Developmental Biology (5th ed.). Philadelphia, Pa.: Elsevier/Saunders. ISBN 978-1-4557-2797-1. <a href="978-1-4557-2797-1" target="_blank">978-1-4557-2797-1</a> <a href="#fnref:14" class="footnote-back-ref">↩</a></p></li> <li id="fn:15"><p>Carlson BM (2014). Human Embryology and Developmental Biology (5th ed.). Philadelphia, Pa.: Elsevier/Saunders. ISBN 978-1-4557-2797-1. <a href="978-1-4557-2797-1" target="_blank">978-1-4557-2797-1</a> <a href="#fnref:15" class="footnote-back-ref">↩</a></p></li> <li id="fn:16"><p>Harvey RP (February 1999). "Seeking a regulatory roadmap for heart morphogenesis". Seminars in Cell & Developmental Biology. 10 (1): 99–107. doi:10.1006/scdb.1998.0277. PMID 10355034. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:16" class="footnote-back-ref">↩</a></p></li> <li id="fn:17"><p>Togi K, Kawamoto T, Yamauchi R, Yoshida Y, Kita T, Tanaka M (June 2004). "Role of Hand1/eHAND in the dorso-ventral patterning and interventricular septum formation in the embryonic heart". Molecular and Cellular Biology. 24 (11): 4627–35. doi:10.1128/MCB.24.11.4627-4635.2004. PMC 416422. 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