{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T02:59:58Z","timestamp":1792724398143,"version":"4.5.0"},"reference-count":75,"publisher":"Cold Spring Harbor Laboratory","issue":"13","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes Dev."],"published-print":{"date-parts":[[1995,7,1]]},"abstract":"<jats:p>The murine homeo box gene Nkx2-5 is expressed in precardiac mesoderm and in the myocardium of embryonic and fetal hearts. Targeted interruption of Nkx2-5 resulted in abnormal heart morphogenesis, growth retardation and embryonic lethality at approximately 9-10 days postcoitum (p.c.). Heart tube formation occurred normally in mutant embryos, but looping morphogenesis, a critical determinant of heart form, was not initiated at the linear heart tube stage (8.25-8.5 days p.c.). Commitment to the cardiac muscle lineage, expression of most myofilament genes and myofibrillogenesis were not compromised. However, the myosin light-chain 2V gene (MLC2V) was not expressed in mutant hearts nor in mutant ES cell-derived cardiocytes. MLC2V expression normally occurs only in ventricular cells and is the earliest known molecular marker of ventricular differentiation. The regional expression in mutant hearts of two other ventricular markers, myosin heavy-chain beta and cyclin D2, indicated that not all ventricle-specific gene expression is dependent on Nkx2-5. The data demonstrate that Nkx2-5 is essential for normal heart morphogenesis, myogenesis, and function. Furthermore, this gene is a component of a genetic pathway required for myogenic specialization of the ventricles.<\/jats:p>","DOI":"10.1101\/gad.9.13.1654","type":"journal-article","created":{"date-parts":[[2007,6,5]],"date-time":"2007-06-05T17:15:46Z","timestamp":1181063746000},"page":"1654-1666","source":"Crossref","is-referenced-by-count":1004,"title":["Myogenic and morphogenetic defects in the heart tubes of murine embryos lacking the homeo box gene Nkx2-5."],"prefix":"10.1101","volume":"9","author":[{"given":"I","family":"Lyons","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L M","family":"Parsons","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L","family":"Hartley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J E","family":"Andrews","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L","family":"Robb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R P","family":"Harvey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"246","published-online":{"date-parts":[[1995,7,1]]},"reference":[{"key":"2021111418233689000_9.13.1654.1","first-page":"2753","article-title":"Multiple regulatory elements contribute differentially to muscle creatine kinase enhancer activity in skeletal and cardiac muscle.","volume":"13","year":"1993","journal-title":"Mol. Cell. Biol."},{"key":"2021111418233689000_9.13.1654.2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.7.7b.1325"},{"key":"2021111418233689000_9.13.1654.3","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(92)90187-H"},{"key":"2021111418233689000_9.13.1654.4","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1242\/dev.118.3.719","article-title":"The gene tinman is required for specification of the heart and visceral muscles in Drosophila.","volume":"118","year":"1993","journal-title":"Development"},{"key":"2021111418233689000_9.13.1654.5","doi-asserted-by":"crossref","unstructured":"Bodmer, R. 1995. Heart development in Drosophila and its relationship to vertebrates. TCM (in press).","DOI":"10.1016\/1050-1738(94)00032-Q"},{"key":"2021111418233689000_9.13.1654.6","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1242\/dev.110.3.661","article-title":"A new homeobox-containing gene, msh-2, is transiently expressed early during mesoderm formation in Drosophila.","volume":"110","year":"1990","journal-title":"Development"},{"key":"2021111418233689000_9.13.1654.7","unstructured":"Bradley, A. 1987. Production and analysis of chimaeric mice. In Teratocarcinomas and embryonic stem cells: A practical approach (ed. E.J. Robertson), pp. 113\u2013151. IRL Press, Washington, DC."},{"key":"2021111418233689000_9.13.1654.8","doi-asserted-by":"publisher","DOI":"10.1016\/0959-437X(94)90142-P"},{"key":"2021111418233689000_9.13.1654.9","first-page":"487","article-title":"A novel basic helix-loop-helix protein expressed in paraxial mesoderm and immature somites of mouse embryos and in heart and skeletal muscle of the adult mouse.","volume":"18D","year":"1994","journal-title":"J. Cell. Biochem."},{"key":"2021111418233689000_9.13.1654.10","doi-asserted-by":"publisher","DOI":"10.1101\/gad.8.19.2293"},{"key":"2021111418233689000_9.13.1654.11","doi-asserted-by":"publisher","DOI":"10.1016\/0003-2697(87)90021-2"},{"key":"2021111418233689000_9.13.1654.12","first-page":"6752","article-title":"Regulation of the human cardiac\/slow-twitch troponin C gene by multiple, cooperative, cell-type-specific, and myoD-responsive elements.","volume":"13","year":"1993","journal-title":"Mol. Cell. Biol."},{"key":"2021111418233689000_9.13.1654.13","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1242\/dev.120.5.1251","article-title":"Mef2 gene expression marks the cardiac and skeletal muscle lineages during mouse embryogenesis.","volume":"120","year":"1994","journal-title":"Development"},{"key":"2021111418233689000_9.13.1654.14","first-page":"4269","article-title":"Heterokaryons of cardiac myocytes and fibroblasts reveal the lack of dominance of the cardiac phenotype.","volume":"14","year":"1994","journal-title":"Mol. Cell. Biol."},{"key":"2021111418233689000_9.13.1654.15","doi-asserted-by":"crossref","first-page":"17234","DOI":"10.1016\/S0021-9258(18)41917-5","article-title":"M-CAT binding factor is related to the SV40 enhancer binding factor, TEF-1.","volume":"267","year":"1992","journal-title":"J. Biol. Chem."},{"key":"2021111418233689000_9.13.1654.16","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90292-5"},{"key":"2021111418233689000_9.13.1654.17","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1242\/dev.114.1.173","article-title":"The involvement of adherens junction components in myofibrillogenesis in cultured cardiac myocytes.","volume":"114","year":"1992","journal-title":"Development"},{"key":"2021111418233689000_9.13.1654.18","first-page":"3115","article-title":"A hormone-encoding gene identifies a pathway for cardiac but Not skeletal muscle gene transcription.","volume":"14","year":"1994","journal-title":"Mol. Cell. Biol."},{"key":"2021111418233689000_9.13.1654.19","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90110-C"},{"key":"2021111418233689000_9.13.1654.20","doi-asserted-by":"crossref","first-page":"12813","DOI":"10.1016\/S0021-9258(18)98762-4","article-title":"Egr-1, a serum-inducible zinc finger protein, regulates transcription of the rat cardiac \u03b1-myosin heavy chain gene.","volume":"266","year":"1991","journal-title":"J. Biol. Chem."},{"key":"2021111418233689000_9.13.1654.21","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.1994.1206"},{"key":"2021111418233689000_9.13.1654.22","doi-asserted-by":"publisher","DOI":"10.1007\/BF00292022"},{"key":"2021111418233689000_9.13.1654.23","doi-asserted-by":"publisher","DOI":"10.1038\/326292a0"},{"key":"2021111418233689000_9.13.1654.24","first-page":"29","article-title":"Actin bundles on the right side in the caudal part of the heart tube play a role in dextro-looping in the embryonic chick heart.","volume":"183","year":"1991","journal-title":"Anat. Embryol."},{"key":"2021111418233689000_9.13.1654.25","doi-asserted-by":"publisher","DOI":"10.1038\/ng0794-353"},{"key":"2021111418233689000_9.13.1654.26","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1242\/dev.104.3.341","article-title":"Features of embryonic induction.","volume":"104","year":"1988","journal-title":"Development"},{"key":"2021111418233689000_9.13.1654.27","doi-asserted-by":"publisher","DOI":"10.1126\/science.7973707"},{"key":"2021111418233689000_9.13.1654.28","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.86.20.7716"},{"key":"2021111418233689000_9.13.1654.29","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.17.8145"},{"key":"2021111418233689000_9.13.1654.30","doi-asserted-by":"crossref","first-page":"16961","DOI":"10.1016\/S0021-9258(19)89483-8","article-title":"Chamber specification of atrial myosin light chain-2 expression precedes septation during murine cardiogenesis.","volume":"269","year":"1994","journal-title":"J. Biol. Chem."},{"key":"2021111418233689000_9.13.1654.31","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/19.15.4293"},{"key":"2021111418233689000_9.13.1654.32","doi-asserted-by":"publisher","DOI":"10.1016\/0955-0674(94)90037-X"},{"key":"2021111418233689000_9.13.1654.33","unstructured":"Layton, W.M., M.D. Manasek, and D.M.D. Manasek. 1980. Cardiac looping in early iv\/iv mouse embryos. In Etiology and morphogenesis of congenital heart disease (ed. R. Van Pragh), pp. 109\u2013126. Futura, Mount Kisco, New York."},{"key":"2021111418233689000_9.13.1654.34","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1242\/dev.119.2.419","article-title":"Nkx-2.5: A novel murine homeobox gene expressed in early heart progenitor cells and their myogenic descendants.","volume":"119","year":"1993","journal-title":"Development"},{"key":"2021111418233689000_9.13.1654.35","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.1993.1088"},{"key":"2021111418233689000_9.13.1654.36","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1242\/dev.118.3.865","article-title":"Induction of cardiac muscle differentiation in isolated animal pole explants of Xenopus laevis embryos.","volume":"118","year":"1993","journal-title":"Development"},{"key":"2021111418233689000_9.13.1654.37","first-page":"70","article-title":"In situ analysis of the cardiac muscle gene program during embryogenesis.","volume":"4","year":"1994","journal-title":"TCM"},{"key":"2021111418233689000_9.13.1654.38","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.111.6.2427"},{"key":"2021111418233689000_9.13.1654.39","doi-asserted-by":"publisher","DOI":"10.1021\/bi00570a013"},{"key":"2021111418233689000_9.13.1654.40","unstructured":"Manasek, F.J. 1976. Interactions involved in cardiac morphogenesis. In The cell surface in animal embryogenesis and development (ed. G. Poste, and G.C. Nicholson), pp. 545\u2013598. North-Holland, Amsterdam, Holland."},{"key":"2021111418233689000_9.13.1654.41","doi-asserted-by":"publisher","DOI":"10.1016\/0012-1606(72)90077-2"},{"key":"2021111418233689000_9.13.1654.42","first-page":"161","article-title":"Cyto-differentiation: A causal antecedent of looping?","volume":"14","year":"1978","journal-title":"Birth Defects: Original Article Series"},{"key":"2021111418233689000_9.13.1654.43","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.107.2.573"},{"key":"2021111418233689000_9.13.1654.44","first-page":"2802","article-title":"Duplication CArG box domains have positive and mutually dependent regulatory roles in expression of the human \u03b1-cardiac actin gene.","volume":"7","year":"1987","journal-title":"Mol. Cell. Biol."},{"key":"2021111418233689000_9.13.1654.45","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1242\/dev.119.2.485","article-title":"Defects in heart and lung development in compound heterozygotes for two different targeted mutations at the N-myc locus.","volume":"119","year":"1993","journal-title":"Development"},{"key":"2021111418233689000_9.13.1654.46","doi-asserted-by":"crossref","first-page":"2602","DOI":"10.1016\/S0021-9258(18)53817-5","article-title":"Expression of the \u03b1-myosin heavy chain gene in the heart is regulated in part by and E-box-dependent mechanism.","volume":"268","year":"1993","journal-title":"J. Biol. Chem."},{"key":"2021111418233689000_9.13.1654.47","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.1994.1180"},{"key":"2021111418233689000_9.13.1654.48","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(89)90434-0"},{"key":"2021111418233689000_9.13.1654.49","first-page":"1469","article-title":"A ubiquitous factor (Hf-1a) and a distinct muscle factor (Hf-1b\/MEF2) form an E-box-independent pathway for cardiac muscle gene expression.","volume":"12","year":"1992","journal-title":"Mol. Cell. Biol."},{"key":"2021111418233689000_9.13.1654.50","first-page":"7331","article-title":"The basic helix-loop-helix protein upstream stimulating factor regulates the cardiac ventricular myosin light-chain 2 gene via independent cis regulatory elements.","volume":"14","year":"1994","journal-title":"Mol. Cell. Biol."},{"key":"2021111418233689000_9.13.1654.51","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.11.5157"},{"key":"2021111418233689000_9.13.1654.52","doi-asserted-by":"crossref","first-page":"2175","DOI":"10.1242\/dev.120.8.2175","article-title":"The Caenorhabditis elegans NK-2 class homeoprotein CEH-22 is involved in combinatorial activation of gene expression in pharyngeal muscle.","volume":"120","year":"1994","journal-title":"Development"},{"key":"2021111418233689000_9.13.1654.53","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.72.1.1"},{"key":"2021111418233689000_9.13.1654.54","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1101\/gad.8.1.1","article-title":"bHLH factors in muscle development: Deadlines and commitment, what to leave in and what to leave out.","volume":"8","year":"1994","journal-title":"Genes & Dev."},{"key":"2021111418233689000_9.13.1654.55","first-page":"1967","article-title":"Identification and characterization of a cardiac-specific transcriptional regulatory element in the slow\/cardiac troponin C gene.","volume":"12","year":"1992","journal-title":"Mol. Cell. Biol."},{"key":"2021111418233689000_9.13.1654.56","doi-asserted-by":"crossref","first-page":"11905","DOI":"10.1016\/S0021-9258(19)38485-6","article-title":"Mouse embryonic stem cells express the cardiac myosin heavy chain genes during development in vitro.","volume":"265","year":"1990","journal-title":"J. Biol. Chem."},{"key":"2021111418233689000_9.13.1654.57","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90621-V"},{"key":"2021111418233689000_9.13.1654.58","doi-asserted-by":"publisher","DOI":"10.1016\/S0074-7696(08)60228-4"},{"key":"2021111418233689000_9.13.1654.59","doi-asserted-by":"publisher","DOI":"10.1101\/gad.8.11.1311"},{"key":"2021111418233689000_9.13.1654.60","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.9.4047"},{"key":"2021111418233689000_9.13.1654.61","doi-asserted-by":"publisher","DOI":"10.1016\/0012-1606(90)90083-U"},{"key":"2021111418233689000_9.13.1654.62","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1242\/dev.108.3.461","article-title":"The role of the dorsal lip in induction of heart mesoderm in Xenopus laevis.","volume":"108","year":"1990","journal-title":"Development"},{"key":"2021111418233689000_9.13.1654.63","doi-asserted-by":"publisher","DOI":"10.1126\/science.8197461"},{"key":"2021111418233689000_9.13.1654.64","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90001-9"},{"key":"2021111418233689000_9.13.1654.65","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1242\/dev.104.3.431","article-title":"The localization of laminin mRNA and protein in the postimplantation embryo and placenta of the mouse: An in situ and immunocytochemical study.","volume":"104","year":"1988","journal-title":"Development"},{"key":"2021111418233689000_9.13.1654.66","first-page":"503","article-title":"Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells.","volume":"51","year":"1986","journal-title":"Cell"},{"key":"2021111418233689000_9.13.1654.67","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.1994.1089"},{"key":"2021111418233689000_9.13.1654.68","first-page":"1264","article-title":"Different regulatory sequences control creatine kinase-M gene expression in directly injected skeletal and cardiac muscle.","volume":"13","year":"1993","journal-title":"Mol. Cell. Biol."},{"key":"2021111418233689000_9.13.1654.69","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-5320(73)80002-4"},{"key":"2021111418233689000_9.13.1654.70","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.86.14.5434"},{"key":"2021111418233689000_9.13.1654.71","doi-asserted-by":"publisher","DOI":"10.1126\/science.1846704"},{"key":"2021111418233689000_9.13.1654.72","unstructured":"Wilkinson, D.G. 1992. Whole mount in situ hybridization of vertebrate embryos. In In situ hybridization: A practical approach (ed. D.G. Wilkinson), pp. 75\u201384. Oxford University Press, Oxford, UK."},{"key":"2021111418233689000_9.13.1654.73","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-0436.1991.tb00255.x"},{"key":"2021111418233689000_9.13.1654.74","unstructured":"Wurst, W. and A. Joyner. 1993. Production of targeted embryonic stem cell clones. In Gene targeting a practical approach (ed. A.L. Joyner), pp. 33\u201361. Oxford University Press, New York."},{"key":"2021111418233689000_9.13.1654.75","first-page":"4432","article-title":"A novel, tissue-restricted zinc finger protein (HF-1b) binds to the cardiac regulatory element (HF-1B\/MEF-2) in the rat myosin light-chain 2 gene.","volume":"13","year":"1993","journal-title":"Mol. Cell. Biol."}],"container-title":["Genes &amp; Development"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/gad.9.13.1654","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,14]],"date-time":"2021-11-14T21:36:52Z","timestamp":1636925812000},"score":1,"resource":{"primary":{"URL":"http:\/\/genesdev.cshlp.org\/lookup\/doi\/10.1101\/gad.9.13.1654"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1995,7,1]]},"references-count":75,"journal-issue":{"issue":"13","published-print":{"date-parts":[[1995,7,1]]}},"alternative-id":["10.1101\/gad.9.13.1654"],"URL":"https:\/\/doi.org\/10.1101\/gad.9.13.1654","relation":{},"ISSN":["0890-9369","1549-5477"],"issn-type":[{"value":"0890-9369","type":"print"},{"value":"1549-5477","type":"electronic"}],"subject":[],"published":{"date-parts":[[1995,7,1]]}}}