Advertisement

pp 1-24 | Cite as

Homeobox Genes and Homeodomain Proteins: New Insights into Cardiac Development, Degeneration and Regeneration

  • Rokas Miksiunas
  • Ali Mobasheri
  • Daiva BironaiteEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series

Abstract

Cardiovascular diseases are the most common cause of human death in the developing world. Extensive evidence indicates that various toxic environmental factors and unhealthy lifestyle choices contribute to the risk, incidence and severity of cardiovascular diseases. Alterations in the genetic level of myocardium affects normal heart development and initiates pathological processes leading to various types of cardiac diseases. Homeobox genes are a large and highly specialized family of closely related genes that direct the formation of body structure, including cardiac development. Homeobox genes encode homeodomain proteins that function as transcription factors with characteristic structures that allow them to bind to DNA, regulate gene expression and subsequently control the proper physiological function of cells, tissues and organs. Mutations in homeobox genes are rare and usually lethal with evident alterations in cardiac function at or soon after the birth. Our understanding of homeobox gene family expression and function has expanded significantly during the recent years. However, the involvement of homeobox genes in the development of human and animal cardiac tissue requires further investigation. The phenotype of human congenital heart defects unveils only some aspects of human heart development. Therefore, mouse models are often used to gain a better understanding of human heart function, pathology and regeneration. In this review, we have focused on the role of homeobox genes in the development and pathology of human heart as potential tools for the future development of targeted regenerative strategies for various heart malfunctions.

Keywords

Cardiac development Cardiac regeneration Heart disease Homeobox genes 

Abbreviations

AMHC1

atrial myosin heavy chain-1

ANTP

Antennapedia

BMP

bone morphogenetic protein

Cdh2

cadherin 2

CDK

cyclin-dependent kinases

Cited2

Cbp/P300 interacting transactivator with Glu/Asp Rich Carboxy-Terminal Domain 2

CNS

central nerve system

ESC

embryonic stem cells

FGF

fibroblast growth factor

FHF

first heart field

Flk1

fetal liver kinase 1

GJA5

gap junction protein alpha 5

GSC

goosecoid

H3K27me3

histone H3 methylation on the amino (N) terminal tail

Hcn4

hyperpolarization-activated cyclic nucleotide-gated channel 4 gene

HOXL

homeobox transcription factor Hox-like

Irx

Iroquois family of homeobox genes

ISL1

LIM-homeodomain transcription factor islet 1/insulin gene enhancer protein ISL-1

JMJD3

JmjC domain-containing protein 3

MEF2C

myocyte-specific enhancer factor 2C

MESP1

mesoderm posterior BHLH transcription factor 1

MSCs

mesenchymal stem cells

Myocd

myocardin

NKL

NK-like

Nkx2-5

homeobox protein NK-2 homolog E

Nodal

nodal growth differentiation factor

Nppa

natriuretic peptide A

OFT

outflow tract

PCBP2

poly(rC)-binding protein 2

Pitx2

paired like homeodomain 2

Pitx2c

paired-like homeodomain transcription factor 2

PROS

prospero

RA

retinoic acid

SAN

sinoatrial node

SHF

second heart field

Shox2

short stature homeobox 2

SMAD

main signal transducers for receptors of the transforming growth factor beta (TGF-β) superfamily;

TALE

three-amino-acid loop extension

Tbx5

T-box transcription factor 5

TF

transcription factors

TGF-β

transforming growth factor beta;

VCS

ventricular conduction system

ZEB2

zinc finger E-box binding homeobox 2

ZF

zinc finger

Ziro

zebrafish iroquois homeobox genes

ZO-3

tight junction protein 3

Notes

Acknowledgements

The study is funded by the Lithuanian Research council, project No. S-MIP-17-13.

Ethics Approval and Consent to Participate

Not applicable.

Consent for Publication

All authors agree to the publication of this manuscript.

Availability of Data and Material

Not applicable.

Competing Interests

The authors declare that they have no competing interests.

Authors’ Contributions

RM wrote the manuscript draft. DB revised the manuscript. AM read, corrected and approved the final manuscript.

Funding

The study is funded by the Lithuanian Research council, project No. S-MIP-17-13.

References

  1. Akazawa H, Komuro I (2005) Cardiac transcription factor Csx/Nkx2-5: its role in cardiac development and diseases. Pharmacol Ther 107:252–268.  https://doi.org/10.1016/j.pharmthera.2005.03.005CrossRefGoogle Scholar
  2. Alig J, Marger L, Mesirca P, Ehmke H, Mangoni ME, Isbrandt D (2009) Control of heart rate by cAMP sensitivity of HCN channels. Proc Natl Acad Sci U S A 106:12189–12194.  https://doi.org/10.1073/pnas.0810332106CrossRefGoogle Scholar
  3. Allen BG, Allen-Brady K, Weeks DL (2006) Reduction of XNkx2-10 expression leads to anterior defects and malformation of the embryonic heart. Mech Dev 123:719–729.  https://doi.org/10.1016/j.mod.2006.07.008CrossRefGoogle Scholar
  4. Anderson DJ, Kaplan DI, Bell KM, Koutsis K, Haynes JM, Mills RJ, Phelan DG, Qian EL, Leitoguinho AR, Arasaratnam D, Labonne T, Ng ES, Davis RP, Casini S, Passier R, Hudson JE, Porrello ER, Costa MW, Rafii A, Curl CL, Delbridge LM et al (2018) NKX2-5 regulates human cardiomyogenesis via a HEY2 dependent transcriptional network. Nat Commun 9:1–13.  https://doi.org/10.1038/s41467-018-03714-xCrossRefGoogle Scholar
  5. Arrington CB, Dowse BR, Bleyl SB, Bowles NE (2012) Non-synonymous variants in pre-B cell leukemia homeobox (PBX) genes are associated with congenital heart defects. Eur J Med Genet 55:235–237.  https://doi.org/10.1016/j.ejmg.2012.02.002.Non-synonymousCrossRefGoogle Scholar
  6. Azcoitia V, Aracil M, Martínez-A C, Torres M (2005) The homeodomain protein Meis1 is essential for definitive hematopoiesis and vascular patterning in the mouse embryo. Dev Biol 280:307–320.  https://doi.org/10.1016/j.ydbio.2005.01.004CrossRefGoogle Scholar
  7. Bao ZZ, Bruneau BG, Seidman JG, Seidman CE, Cepko CL (1999) Regulation of chamber-specific gene expression in the developing heart by irx4. Science 283:1161–1164Google Scholar
  8. Bedford FK, Ashworth A, Enver T, Wiedemann LM (1993) HEX: a novel homeobox gene expressed during haematopoiesis and conserved between mouse and human. Nucleic Acids Res 21:1245–1249Google Scholar
  9. Belaguli NS, Sepulveda JL, Nigam V, Charron F, Nemer M, Schwartz RJ (2000) Cardiac tissue enriched factors serum response factor and GATA-4 are mutual coregulators. Mol Cell Biol 20:7550–7558Google Scholar
  10. Benchabane H, Wrana JL (2003) GATA- and Smad1-dependent enhancers in the Smad7 gene differentially interpret bone morphogenetic protein concentrations. Mol Cell Biol 23:6646–6661Google Scholar
  11. Benson DW (2002) The genetics of congenital heart disease: a point in the revolution. Cardiol Clin 20:385–394Google Scholar
  12. Bergwerff M, Gittenberger-de Groot AC, Wisse LJ, DeRuiter MC, Wessels A, Martin JF, Olson EN, Kern MJ (2000) Loss of function of the Prx1 and Prx2 homeobox genes alters architecture of the great elastic arteries and ductus arteriosus. Virchows Arch 436:12–19Google Scholar
  13. Bertrand N, Roux M, Ryckebüsch L, Niederreither K, Dollé P, Moon A, Capecchi M, Zaffran S (2011) Hox genes define distinct progenitor sub-domains within the second heart field. Dev Biol 353:266–274.  https://doi.org/10.1016/j.ydbio.2011.02.029CrossRefGoogle Scholar
  14. Blaschke RJ, Hahurij ND, Kuijper S, Just S, Wisse LJ, Deissler K, Maxelon T, Anastassiadis K, Spitzer J, Hardt SE, Schöler H, Feitsma H, Rottbauer W, Blum M, Meijlink F, Rappold G, Gittenberger-de Groot AC (2007) Targeted mutation reveals essential functions of the homeodomain transcription factor Shox2 in sinoatrial and pacemaking development. Circulation 115:1830–1838.  https://doi.org/10.1161/CIRCULATIONAHA.106.637819CrossRefGoogle Scholar
  15. Bosley TM, Alorainy IA, Salih MA, Aldhalaan HM, Abu-Amero KK, Oystreck DT, Tischfield MA, Engle EC, Erickson RP (2008) The clinical spectrum of homozygous HOXA1 mutations. Am J Med Genet A 146:1235–1240.  https://doi.org/10.1002/ajmg.a.32262CrossRefGoogle Scholar
  16. Brand T, Andrée B, Schneider A, Buchberger A, Arnold H (1997) Chicken NKx2-8, a novel homeobox gene expressed during early heart and foregut development. Mech Dev 64:53–59Google Scholar
  17. Bruneau BG, Nemer G, Schmitt JP, Charron F, Robitaille L, Caron S, Conner DA, Gessler M, Nemer M, Seidman CE, Seidman JG (2001a) A murine model of Holt-Oram syndrome defines roles of the T-box transcription factor Tbx5 in cardiogenesis and disease. Cell 106:709–721Google Scholar
  18. Bruneau BG, Bao ZZ, Fatkin D, Xavier-Neto JGD, Maguire CT, Berul CI, Kass DA, Kuroski-de Bold ML, de Bold AJ, Conner DA, Rosenthal N, Cepko CL, Seidman CE, Seidman JG (2001b) Cardiomyopathy in irx4-deficient mice is preceded by abnormal ventricular gene expression. Mol Cell Biol 21:1730–1736.  https://doi.org/10.1128/MCB.21.5.1730-1736.2001CrossRefGoogle Scholar
  19. Buckingham M, Meilhac S, Zaffran S (2005) Building the mammalian heart from two sources of myocardial cells. Nat Rev Genet 6:826–837.  https://doi.org/10.1038/nrg1710CrossRefGoogle Scholar
  20. Bürglin TR, Affolter M (2016) Homeodomain proteins: an update. Chromosoma 125:497–521.  https://doi.org/10.1007/s00412-015-0543-8CrossRefGoogle Scholar
  21. Busser BW, Lin Y, Yang Y et al (2015) An orthologous epigenetic gene expression signature derived from differentiating embryonic stem cells identifies regulators of cardiogenesis. PLoS One 10:e0141066.  https://doi.org/10.1371/journal.pone.0141066CrossRefGoogle Scholar
  22. Cai CL, Liang X, Shi Y, Chu PH, Pfaff SL, Chen J, Evans S (2003) Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Dev Cell 5:877–889Google Scholar
  23. Camacho P, Fan H, Liu Z, He J (2016) Small mammalian animal models of heart disease. Am J Cardiovasc Dis 6:70–80Google Scholar
  24. Cambier L, Plate M, Sucov HM, Pashmforoush M (2014) Nkx2-5 regulates cardiac growth through modulation of Wnt signaling by R-spondin3. Development 141:2959–2971.  https://doi.org/10.1242/dev.103416CrossRefGoogle Scholar
  25. Campione M, Steinbeisser H, Schweickert A, Deissler K, van Bebber F, Lowe LA, Nowotschin S, Viebahn C, Haffter P, Kuehn MR, Blum M (1999) The homeobox gene Pitx2: mediator of asymmetric left-right signaling in vertebrate heart and gut looping. Development 126:1225–1234Google Scholar
  26. Cavodeassi F, Modolell J, Gómez-Skarmeta JL (2001) The Iroquois family of genes: from body building to neural patterning. Development 128:2847–2855Google Scholar
  27. Chang CP, Stankunas K, Shang C, Kao SC, Twu KY, Cleary ML (2008) Pbx1 functions in distinct regulatory networks to pattern the great arteries and cardiac outflow tract. Development 135:3577–3586.  https://doi.org/10.1242/dev.022350CrossRefGoogle Scholar
  28. Chen F, Kook H, Milewski R, Gitler AD, Lu MM, Li J, Nazarian R, Schnepp R, Jen K, Biben C, Runke G, Mackay JP, Novotny J, Schwartz RJ, Harvey RP, Mullins MC, Epstein JA (2002) Hop is an unusual homeobox gene that modulates cardiac development. Cell 110:713–723Google Scholar
  29. Chen YH, Ishii M, Sun J, Sucov HM, Maxson RE Jr (2007) Msx1 and Msx2 regulate survival of secondary heart field precursors and post-migratory proliferation of cardiac neural crest in the outflow tract. Dev Biol 308:421–437.  https://doi.org/10.1016/j.ydbio.2007.05.037CrossRefGoogle Scholar
  30. Chen Y, Yang L, Cui T, Pacyna-Gengelbach M, Petersen I (2015) Hopx is methylated and exerts tumour-suppressive function through ras-induced senescence in human lung cancer. J Pathol 235:397–407.  https://doi.org/10.1002/path.4469CrossRefGoogle Scholar
  31. Cheng CW, Chow RL, Lebel M, Sakuma R, Cheung HO, Thanabalasingham V, Zhang X, Bruneau BG, Birch DG, Hui CC, McInnes RR, Cheng S (2005) The Iroquois homeobox gene, Irx5, is required for retinal cone bipolar cell development. Dev Biol 287:48–60.  https://doi.org/10.1016/j.ydbio.2005.08.029CrossRefGoogle Scholar
  32. Cheng Z, Wang J, Su D, Pan H, Huang G, Li X, Li Z, Shen A, Xie X, Wang B, Ma X (2011) Two novel mutations of the IRX4 gene in patients with congenital heart disease. Hum Genet 130:657–662.  https://doi.org/10.1007/s00439-011-0996-7CrossRefGoogle Scholar
  33. Christoffels VM, Keijser AG, Houweling AC, Clout DE, Moorman AFM (2000) Patterning the embryonic heart: identification of five mouse Iroquois homeobox genes in the developing heart. Dev Biol 224:263–274.  https://doi.org/10.1006/dbio.2000.9801CrossRefGoogle Scholar
  34. Costantini DL, Arruda EP, Agarwal P, Kim KH, Zhu Y, Zhu W, Lebel M, Cheng CW, Park CY, Pierce SA, Guerchicoff A, Pollevick GD, Chan TY, Kabir MG, Cheng SH, Husain M, Antzelevitch C, Srivastava D, Gross GJ, Hui CC, Backx PH, Bruneau BG (2005) The homeodomain transcription factor Irx5 establishes the mouse cardiac ventricular repolarization gradient. Cell 123:347–358.  https://doi.org/10.1016/j.cell.2005.08.004CrossRefGoogle Scholar
  35. Date Y, Hasegawa S, Yamada T, Inoue Y, Mizutani H, Nakata S, Akamatsu H (2013) Major amino acids in collagen hydrolysate regulate the differentiation of mouse embryoid bodies. J Biosci Bioeng 116:386–390.  https://doi.org/10.1016/j.jbiosc.2013.03.014CrossRefGoogle Scholar
  36. Dorn T, Goedel A, Lam JT, Haas J, Tian Q, Herrmann F, Bundschu K, Dobreva G, Schiemann M, Dirschinger R, Guo Y, Kühl SJ, Sinnecker D, Lipp P, Laugwitz K-L, Kühl M, Moretti A (2015) Direct Nkx2-5 transcriptional repression of isl1 controls cardiomyocyte subtype identity. Stem Cells 33:1113–1129.  https://doi.org/10.1002/stem.1923CrossRefGoogle Scholar
  37. Douville JM, Cheung DY, Herbert KL, Moffatt T, Wigle JT (2011) Mechanisms of MEOX1 and MEOX2 regulation of the cyclin dependent kinase inhibitors p21 and p16 in vascular endothelial cells. PLoS One 6:e29099.  https://doi.org/10.1371/journal.pone.0029099CrossRefGoogle Scholar
  38. Dupays L, Shang C, Wilson R, Kotecha S, Wood S, Towers N, Mohun T (2015) Sequential binding of MEIS1 and NKX2-5 on the Popdc2 gene: a mechanism for spatiotemporal regulation of enhancers during cardiogenesis. Cell Rep 13:183–195.  https://doi.org/10.1016/j.celrep.2015.08.065CrossRefGoogle Scholar
  39. Dyer LA, Kirby ML (2009) The role of secondary heart field in cardiac development. Dev Biol 336:137–144.  https://doi.org/10.1016/j.ydbio.2009.10.009CrossRefGoogle Scholar
  40. Elsir T, Smits A, Lindström MS, Nister M (2012) Transcription factor PROX1: its role in development and cancer. Cancer Metastasis Rev 31:793–805.  https://doi.org/10.1007/s10555-012-9390-8CrossRefGoogle Scholar
  41. Espinoza-Lewis RA, Yu L, He F, Liu H, Tang R, Shi J, Sun X, Martin JF, Wang D, Yang J, Chen Y (2009) Shox2 is essential for the differentiation of cardiac pacemaker cells by repressing Nkx2-5. Dev Biol 327:376–385.  https://doi.org/10.1021/nl061786n.Core-ShellCrossRefGoogle Scholar
  42. Espinoza-Lewis RA, Liu H, Sun C, Chen C, Jiao K, Chen Y (2011) Ectopic expression of Nkx2.5 suppresses the formation of the sinoatrial node in mice. Dev Biol 356:359–369.  https://doi.org/10.1016/j.ydbio.2011.05.663CrossRefGoogle Scholar
  43. Epstein JA (1996) Pax3, neural crest and cardiovascular development. Trends Cardiovasc Med 6:255–260.  https://doi.org/10.1016/S1050-1738(96)00110-7CrossRefGoogle Scholar
  44. Evans AL, Gage PJ (2005) Expression of the homeobox gene Pitx2 in neural crest is required for optic stalk and ocular anterior segment development. Hum Mol Genet 14:3347–3359.  https://doi.org/10.1093/hmg/ddi365CrossRefGoogle Scholar
  45. Feng Y, Yang P, Luo S, Zhang Z, Li H, Zhu P, Song Z (2016) Shox2 influences mesenchymal stem cell fate in a co-culture model in vitro. Mol Med Rep 14:637–642.  https://doi.org/10.3892/mmr.2016.5306CrossRefGoogle Scholar
  46. Franco D, Sedmera D, Lozano-Velasco E (2017) Multiple roles of Pitx2 in cardiac development and disease. J Cardiovasc Dev Dis 4:16.  https://doi.org/10.3390/jcdd4040016CrossRefGoogle Scholar
  47. Gao XR, Tan YZ, Wang HJ (2011) Overexpression of Csx/Nkx2.5 and GATA-4 enhances the efficacy of mesenchymal stem cell transplantation after myocardial infarction. Circ J 75:2683–2691.  https://doi.org/10.1253/circj.CJ-11-0238CrossRefGoogle Scholar
  48. Garavelli L, Mainardi PC (2007) Mowat-Wilson syndrome. Orphanet J Rare Dis 12:1–12.  https://doi.org/10.1186/1750-1172-2-42CrossRefGoogle Scholar
  49. Garavelli L, Ivanovski I, Caraffi SG, Santodirocco D, Pollazzon M, Cordelli DM, Abdalla E, Accorsi P, Adam MP, Baldo C, Bayat A, Belligni E, Bonvicini F, Breckpot J, Callewaert B, Cocchi G, Cuturilo G, Devriendt K, Dinulos MB, Djuric O et al (2017) Neuroimaging findings in Mowat – Wilson syndrome: a study of 54 patients. Genet Med 19:691–700.  https://doi.org/10.1038/gim.2016.176CrossRefGoogle Scholar
  50. Gheldof A, Hulpiau P, van Roy F, De Craene B, Berx G (2012) Evolutionary functional analysis and molecular regulation of the ZEB transcription factors. Cell Mol Life Sci 69:2527–2541.  https://doi.org/10.1007/s00018-012-0935-3CrossRefGoogle Scholar
  51. Gill HK, Parsons SR, Spalluto C, Davies AF, Knorz VJ, Burlinson CE, Ng B, Carter NP, Ogilvie CM, Wilson DI, Roberts RG (2009) Separation of the PROX1 gene from upstream conserved elements in a complex inversion/translocation patient with hypoplastic left heart. Eur J Hum Genet 17:1423–1431.  https://doi.org/10.1038/ejhg.2009.91CrossRefGoogle Scholar
  52. Gómez-Skarmeta JL, Modolell J (2002) Iroquois genes: genomic organization and function in vertebrate neural development. Curr Opin Genet Dev 12:403–408Google Scholar
  53. Gong LG, Qiu GR, Jiang H, Xu XY, Zhu HY, Sun KL (2005) Analysis of single nucleotide polymorphisms and haplotypes in HOXC gene cluster within susceptible region 12q13 of simple congenital heart disease. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 22:497–501Google Scholar
  54. Gu S, Wei N, Yu L, Fei J, Chen Y (2008) Shox2-deficiency leads to dysplasia and ankylosis of the temporomandibular joint in mice. Mech Dev 125:729–742.  https://doi.org/10.1016/j.mod.2008.04.003CrossRefGoogle Scholar
  55. Guddati AK, Otero JJ, Kessler E, Aistrup G, Wasserstrom JA, Han X, Lomasney JW, Kessler JA (2009) Embryonic stem cells overexpressing Pitx2 engraft in infarcted myocardium and improve cardiac function. Int Heart J 50:783–799Google Scholar
  56. Güleç Ç, Abacı N, Bayrak F, Kömürcü Bayrak E, Kahveci G, Güven C, Ünaltuna NE (2014) Association between non-coding polymorphisms of HOPX gene and syncope in hypertrophic cardiomyopathy. Anadolu Kardiyol Derg 14:617–624.  https://doi.org/10.5152/akd.2014.4972CrossRefGoogle Scholar
  57. Guo C, Wang Q, Wang Y, Yang L, Luo H, Cao XF, An L, Qiu Y, Du M, Ma X, Hui L, Lu C (2017) Exome sequencing reveals novel IRXI mutation in congenital heart disease. Mol Med Rep 15:3193–3197.  https://doi.org/10.3892/mmr.2017.6410CrossRefGoogle Scholar
  58. Haas J, Frese KS, Park YJ, Keller A, Vogel B, Lindroth AM, Weichenhan D, Franke J, Fischer S, Bauer A, Marquart S, Sedaghat-Hamedani FKE, Köhler D, Wolf NM, Hassel S, Nietsch R, Wieland T, Ehlermann P, Schultz JH, Dösch A, Mereles D, Hardt S, Backs J, Hoheisel JD, Plass C, Katus HA, Meder B (2013) Alterations in cardiac DNA methylation in human dilated cardiomyopathy. EMBO Mol Med 5:413–429.  https://doi.org/10.1002/emmm.201201553CrossRefGoogle Scholar
  59. Hallaq H, Pinter E, Enciso J et al (1998) A null mutation of Hhex results in abnormal cardiac development, defective vasculogenesis and elevated Vegfa levels. Development 131:5197–5209.  https://doi.org/10.1242/dev.01393CrossRefGoogle Scholar
  60. Harvey RP (1996) NK-2 homeobox genes and heart development. Dev Biol 178:203–216Google Scholar
  61. Harvey RP (2002) Patterning the vertebrate heart. Nat Rev Genet 3:544–556.  https://doi.org/10.1038/nrg843CrossRefGoogle Scholar
  62. Hatcher CJ, Diman NY, McDermott DA, Basson CT (2003) Transcription factor cascades in congenital heart malformation. Trends Mol Med 9:512–515Google Scholar
  63. Hegarty SV, Sullivan AM, Keeffe GWO (2015) Progress in Neurobiology Zeb2: a multifunctional regulator of nervous system development. Prog Neurobiol 132:81–95.  https://doi.org/10.1016/j.pneurobio.2015.07.001CrossRefGoogle Scholar
  64. Hiroi Y, Kudoh S, Monzen K, Ikeda Y, Yazaki Y, Nagai R, Komuro I (2001) Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation. Nat Genet 28:276–280.  https://doi.org/10.1038/90123CrossRefGoogle Scholar
  65. Hisa T, Spence SE, Rachel RA, Fujita M, Nakamura T, Ward JM, Devor-Henneman DE, Saiki Y, Kutsuna H, Tessarollo L, Jenkins NA, Copeland NG (2004) Hematopoietic, angiogenic and eye defects in Meis1 mutant animals. EMBO J 23:450–459.  https://doi.org/10.1038/sj.emboj.7600038CrossRefGoogle Scholar
  66. Hoffmann S, Clauss S, Berger IM, Weiß B, Montalbano A, Röth R, Bucher M, Klier I, Wakili R, Seitz H, Schulze-Bahr E, Katus HA, Flachsbart F, Nebel A, Guenther SP, Bagaev E, Rottbauer W, Kääb S, Just S, Rappold G (2016) Coding and non-coding variants in the SHOX2 gene in patients with early-onset atrial fibrillation. Basic Res Cardiol 111:36.  https://doi.org/10.1007/s00395-016-0557-2CrossRefGoogle Scholar
  67. Holland PWH, Booth HAF, Bruford EA (2007) Classification and nomenclature of all human homeobox genes. BMC Biol 5:1–29.  https://doi.org/10.1186/1741-7007-5-47CrossRefGoogle Scholar
  68. Innis JW (1997) Role of HOX genes in human development. Curr Opin Pediatr 9:617–622Google Scholar
  69. Ionta V, Liang W, Kim EH, Rafie R, Giacomello A, Marbán E, Cho C (2015) SHOX2 overexpression favors differentiation of embryonic stem cells into cardiac pacemaker cells, improving biological pacing ability. Stem Cell Reports 4:129–142.  https://doi.org/10.1016/j.stemcr.2014.11.004CrossRefGoogle Scholar
  70. Ismat FA, Zhang M, Kook H, Huang B, Zhou R, Ferrari VA, Epstein JA, Patel VV (2005) Homeobox protein Hop functions in the adult cardiac conduction system. Circ Res 96:898–903.  https://doi.org/10.1161/01.RES.0000163108.47258.f3CrossRefGoogle Scholar
  71. JA E (1996) Pax3, neural crest and cardiovascular development. Trends Cardiovasc Med 6:255–60.  https://doi.org/10.1016/S1050-1738(96)00110-7
  72. Jain R, Li D, Gupta M, Manderfield LJ, Ifkovits JL, Wang Q, Liu F, Liu Y, Poleshko A, Padmanabhan A, Raum JC, Li L, Morrisey EE, Lu MM, Won KJ, Epstein JA (2015) Integration of Bmp and Wnt signaling by Hopx specifies commitment of cardiomyoblasts. Science 348:aaa6071.  https://doi.org/10.1016/j.joca.2015.05.020.OsteoarthriticCrossRefGoogle Scholar
  73. Jensen B, Wang T, Christoffels VM, Moorman AFM (2013a) Evolution and development of the building plan of the vertebrate heart. Biochim Biophys Acta 1833:783–794.  https://doi.org/10.1016/j.bbamcr.2012.10.004CrossRefGoogle Scholar
  74. Jensen B, van den Berg G, van den Doel R, Oostra RJ, Wang T, Moorman AFM (2013b) Development of the hearts of lizards and snakes and perspectives to cardiac evolution. PLoS One 8:e63651.  https://doi.org/10.1371/journal.pone.0063651CrossRefGoogle Scholar
  75. Johansson S, Berland S, Gradek GA, Bongers E, de Leeuw N, Pfundt R, Fannemel M, Rødningen O, Brendehaug A, Haukanes BI, Hovland R, Helland G, Houge G (2014) Haploinsufficiency of MEIS2 is associated with orofacial clefting and learning disability. Am J Med Genet A 164A:1622–1626.  https://doi.org/10.1002/ajmg.a.36498CrossRefGoogle Scholar
  76. Jorgensen JS, Gao L (2005) Irx3 is differentially up-regulated in female gonads during sex determination. Gene Expr Pattern 5:756–762.  https://doi.org/10.1016/j.modgep.2005.04.011CrossRefGoogle Scholar
  77. Kang KW, Lee MJ, Song JA, Jeong JY, Kim YK, Lee C, Kim TH, Kwak KB, Kim OJ, An HJ (2014) Overexpression of goosecoid homeobox is associated with chemoresistance and poor prognosis in ovarian carcinoma. Oncol Rep 32:189–198.  https://doi.org/10.3892/or.2014.3203CrossRefGoogle Scholar
  78. Karamboulas C, Swedani A, Ward C, Al-Madhoun AS, Wilton S, Boisvenue S, Ridgeway AG, Skerjanc IS (2006) HDAC activity regulates entry of mesoderm cells into the cardiac muscle lineage. J Cell Sci 119:4305–4314.  https://doi.org/10.1242/jcs.03185CrossRefGoogle Scholar
  79. Karns R, Succop P, Zhang G, Sun G, Indugula SR, Havas-Augustin D, Novokmet N, Durakovic Z, Milanovic SM, Missoni S, Vuletic S, Chakraborty R, Rudan P, Deka R (2013) Modeling metabolic syndrome through structural equations of metabolic traits, comorbid diseases, and GWAS variants. Obesity 21:745–754.  https://doi.org/10.1002/oby.20445CrossRefGoogle Scholar
  80. Kasahara H, Ueyama T, Wakimoto H, Liu MK, Maguire CT, Converso KL, Kang PM, Manning WJ, Lawitts J, Paul DL, Berul CI, Izumo S (2003) Nkx2.5 homeoprotein regulates expression of gap junction protein connexin 43 and sarcomere organization in postnatal cardiomyocytes. J Mol Cell Cardiol 35:243–256.  https://doi.org/10.1016/S0022-2828(03)00002-6CrossRefGoogle Scholar
  81. Kathiresan S, Srivastava D (2012) Genetics of human cardiovascular disease. Cell 148:1242–1257.  https://doi.org/10.1016/j.cell.2012.03.001CrossRefGoogle Scholar
  82. Kawamura T, Ono K, Morimoto T et al (2005) Acetylation of GATA-4 is involved in the differentiation of embryonic stem cells into cardiac myocytes. J Biol Chem 280:19682–19688.  https://doi.org/10.1074/jbc.M412428200CrossRefGoogle Scholar
  83. Kelliny C, Ekelund U, Andersen LB, Brage S, Loos RJ, Wareham NJ, Langenberg C (2009) Common genetic determinants of glucose homeostasis in healthy children: the European Youth Heart Study. Diabetes 58:2939–2945.  https://doi.org/10.2337/db09-0374CrossRefGoogle Scholar
  84. Kitajima S, Takagi A, Inoue T, Saga Y (2000) MesP1 and MesP2 are essential for the development of cardiac mesoderm. Development 127:3215–3226Google Scholar
  85. Koizumi A, Sasano T, Kimura W, Miyamoto Y, Aiba T, Ishikawa T, Nogami A, Fukamizu S, Sakurada H, Takahashi Y, Nakamura H, Ishikura T, Koseki H, Arimura T, Kimura A, Hirao K, Isobe M, Shimizu W, Miura N, Furukawa T (2016) Genetic defects in a His-Purkinje system transcription factor, IRX3, cause lethal cardiac arrhythmias. Eur Heart J 37:1469–1475.  https://doi.org/10.1093/eurheartj/ehv449CrossRefGoogle Scholar
  86. Kook H, Yung WW, Simpson RJ, Kee HJ, Shin S, Lowry JA, Loughlin FE, Yin Z, Epstein JA, Mackay J (2006) Analysis of the structure and function of the transcriptional coregulator HOP. Biochemistry 45:10584–10590.  https://doi.org/10.1021/bi060641sCrossRefGoogle Scholar
  87. Lage K, Møllgård K, Greenway S, Wakimoto H, Gorham JM, Workman CT, Bendsen E, Hansen NT, Rigina O, Roque FS, Wiese C, Christoffels VM, Roberts AE, Smoot LB, Pu WT, Donahoe PK, Tommerup N, Brunak S, Seidman CE, Seidman JG, Larsen LA (2010) Dissecting spatio-temporal protein networks driving human heart development and related disorders. Mol Syst Biol 6:381.  https://doi.org/10.1038/msb.2010.36CrossRefGoogle Scholar
  88. Larroux C, Fahey B, Degnan SM, Adamski M, Rokhsar DS, Degnan BM (2007) The NK homeobox gene cluster predates the origin of Hox genes. Curr Biol 17:706–710.  https://doi.org/10.1016/j.cub.2007.03.008CrossRefGoogle Scholar
  89. Laugwitz KL, Moretti A, Caron L, Nakano A, Chien KR (2007) Islet1 cardiovascular progenitors: a single source for heart lineages. Development 135:193–205.  https://doi.org/10.1242/dev.001883CrossRefGoogle Scholar
  90. Lebel M, Agarwal P, Cheng CW, Kabir MG, Chan TY, Thanabalasingham V, Zhang X, Cohen DR, Husain M, Cheng SH, Bruneau BG, Cheng SH (2003) The Iroquois homeobox gene irx2 is not essential for normal development of the heart and midbrain-hindbrain boundary in mice. Mol Cell Biol 23:8216–8225Google Scholar
  91. Li J, Cao Y, Wu Y, Chen W, Yuan Y, Ma X, Huang G (2015) The expression profile analysis of NKX2-5 knock-out embryonic mice to explore the pathogenesis of congenital heart disease. J Cardiol 66:527–531.  https://doi.org/10.1016/j.jjcc.2014.12.022CrossRefGoogle Scholar
  92. Liang X, Wang G, Lin L, Lowe J, Zhang Q, Bu L, Chen Y, Chen J, Sun Y, Evans SM (2013) HCN4 dynamically marks the first heart field and conduction system precursors. Circ Res 113:399–407.  https://doi.org/10.1161/CIRCRESAHA.113.301588CrossRefGoogle Scholar
  93. Liang X, Evans SM, Sun Y (2017) Development of the cardiac pacemaker. Cell Mol Life Sci 74:1247–1259.  https://doi.org/10.1007/s00018-016-2400-1CrossRefGoogle Scholar
  94. Lin Q, Schwarz J, Bucana C, Olson EN (1997) Control of mouse cardiac morphogenesis and myogenesis by transcription factor MEF2C. Science 276:1404–1407Google Scholar
  95. Lin CR, Kioussi C, O’Connell S et al (1999) Pitx2 regulates lung asymmetry, cardiac positioning and pituitary and tooth morphogenesis. Nature 401:279–282.  https://doi.org/10.1038/45803CrossRefGoogle Scholar
  96. Lints TJ, Parsons LM, Hartley L, Lyons I, Harvey RP (1993) Nkx-2.5: a novel murine homeobox gene expressed in early heart progenitor cells and their myogenic descendants. Development 119:419–431Google Scholar
  97. Liu CC, Liu WW, Palie JJ et al (2002) Pitx2c patterns anterior myocardium and aortic arch vessels and is required for local cell movement into atrioventricular cushions. Development 129:5081–5091.  https://doi.org/10.1242/dev.00173CrossRefGoogle Scholar
  98. Liu H, Chen CH, Espinoza-Lewis RA, Jiao Z, Sheu I, Hu X, Lin M, Zhang Y, Chen Y (2011) Functional redundancy between human SHOX and mouse Shox2 genes in the regulation of sinoatrial node formation and Pacemaking function *. J Biol Chem 286:17029–17038.  https://doi.org/10.1074/jbc.M111.234252CrossRefGoogle Scholar
  99. Liu Y, Kaneda R, Leja TW, Subkhankulova T, Tolmachov O, Minchiotti G, Schwartz RJ, Barahona M, Schneider M (2014) Hhex and Cer1 mediate the Sox17 pathway for cardiac mesoderm formation in embryonic stem. Stem Cells 32:1515–1526.  https://doi.org/10.1002/stem.1695CrossRefGoogle Scholar
  100. Liu Y, Ni B, Lin Y, Chen XG, Fang Z, Zhao L, Hu Z, Zhang F, Ai X (2014) Genetic polymorphisms in ZFHX3 are associated with atrial fibrillation in a Chinese Han population. PLoS One 9:e101318.  https://doi.org/10.1371/journal.pone.0101318CrossRefGoogle Scholar
  101. Louw JJ, Corveleyn A, Jia Y, Hens G, Gewillig M, Devriendt K (2015) MEIS2 involvement in cardiac development, cleft palate, and intellectual disability. Am J Med Genet A 167A:1142–1146.  https://doi.org/10.1002/ajmg.a.36989CrossRefGoogle Scholar
  102. Lozano-Velasco E, Chinchilla A, Martínez-Fernández S et al (2011) Pitx2c modulates cardiac-specific transcription factors networks in differentiating cardiomyocytes from murine embryonic stem cells. Cells Tissues Organs 194:349–362.  https://doi.org/10.1159/000323533CrossRefGoogle Scholar
  103. Lu D, Wang J, Li J, Guan F, Zhang X, Dong W, Liu N, Gao S, Zhang L (2018) Meox1 accelerates myocardial hypertrophic decompensation through Gata4. Cardiovasc Res 114:300–311.  https://doi.org/10.1093/cvr/cvx222CrossRefGoogle Scholar
  104. Luo ZL, Sun H, Yang ZQ, Ma YH, Gu Y, He YQ, Wei D, Xia LB, Yang BH, Guo T (2014) Genetic variations of ISL1 associated with human congenital heart disease in Chinese Han people. Genet Mol Res 13:1329–1338.  https://doi.org/10.4238/2014.February.28.5CrossRefGoogle Scholar
  105. Luxán G, D’Amato G, de la Pompa JL (2016) Endocardial notch signaling in cardiac development and disease. Circ Res 118:1–18.  https://doi.org/10.1161/CIRCRESAHA.115.305350CrossRefGoogle Scholar
  106. Lyons I, Parsons LM, Hartley L, Li R, Andrews JE, Robb L, Harvey RP (1995) Myogenic and morphogenetic defects in the heart tubes of murine embryos lacking the homeo box gene Nkx2–5. Genes Dev 9:1654–1666Google Scholar
  107. Machon O, Masek J, Machonova O, Krauss S, Kozmik Z (2015) Meis2 is essential for cranial and cardiac neural crest development. BMC Dev Biol 15:40.  https://doi.org/10.1186/s12861-015-0093-6CrossRefGoogle Scholar
  108. Mariotto A, Pavlova O, Park HS, Huber M, Sadek HA (2013) Meis1 regulates postnatal cardiomyocyte cell cycle arrest. Nature 497:249–253.  https://doi.org/10.1038/jid.2014.371CrossRefGoogle Scholar
  109. Mariotto A, Pavlova O, Park HS et al (2016) HOPX: the unusual homeodomain-containing protein. J Invest Dermatol 136:905–911.  https://doi.org/10.1016/j.jid.2016.01.032CrossRefGoogle Scholar
  110. Mathieu ML, Demily C, Chantot-Bastaraud S, Afenjar A, Mignot C, Andrieux J, Gerard M, Catala-Mora J, Jouk PS, Labalme A, Edery P, Sanlaville D, Rossi M (2017) Clinical and molecular cytogenetic characterization of four unrelated patients carrying 2p14 microdeletions. Am J Med Genet A 173:2268–2274.  https://doi.org/10.1002/ajmg.a.38307CrossRefGoogle Scholar
  111. Maves L, Tyler A, Moens CB, Tapscott SJ (2009) Pbx acts with Hand2 in early myocardial differentiation. Dev Biol 333:409–418.  https://doi.org/10.1016/j.ydbio.2009.07.004CrossRefGoogle Scholar
  112. McCulley DJ, Black BL (2012) Transcription factor pathways and congenital heart disease. Curr Top Dev Biol 100:253–277.  https://doi.org/10.1016/B978-0-12-387786-4.00008-7.TranscriptionCrossRefGoogle Scholar
  113. McDonald LA, Gerrelli D, Fok Y, Hurst LD, Tickle C (2010) Comparison of Iroquois gene expression in limbs/fins of vertebrate embryos. J Anat 216:683–691.  https://doi.org/10.1111/j.1469-7580.2010.01233.xCrossRefGoogle Scholar
  114. McElhinney DB, Geiger E, Blinder J, Benson DW, Goldmuntz E (2003) NKX2.5 mutations in patients with congenital heart disease. J Am Coll Cardiol 42:1650–1655Google Scholar
  115. Moorman A, Webb S, Brown NA et al (2003) Development of the heart: (1) formation of the cardiac chambers and arterial trunks. Heart 89:806–814Google Scholar
  116. Nayor M, Vasan RS (2015) Preventing heart failure: the role of physical activity. Curr Opin Cardiol 30:543–550.  https://doi.org/10.1097/HCO.0000000000000206CrossRefGoogle Scholar
  117. Nemer M (2008) Genetic insights into normal and abnormal heart development. Cardiovasc Pathol 17:48–54.  https://doi.org/10.1016/j.carpath.2007.06.005CrossRefGoogle Scholar
  118. Newman CS, Krieg PA (1998) Tinman-related genes expressed during heart development in Xenopus. Dev Genet 22:230–238.  https://doi.org/10.1002/(SICI)1520-6408(1998)22:3<230::AID-DVG5>3.0.CO;2-7CrossRefGoogle Scholar
  119. O’Toole TE, Conklin DJ, Bhatnagar A (2008) Environmental risk factors for heart disease. Rev Environ Health 23:167–202.  https://doi.org/10.1038/nrcardio.2015.152CrossRefGoogle Scholar
  120. Olson EN (2006) Gene regulatory networks in the evolution and development of the heart. Science 313:1922–1927.  https://doi.org/10.1126/science.1132292CrossRefGoogle Scholar
  121. Pearson JC, Lemons D, McGinnis W (2005) Modulating Hox gene functions during animal body patterning. Nat Rev Genet 6:893–904.  https://doi.org/10.1038/nrg1726CrossRefGoogle Scholar
  122. Pechlivanis S, Scherag A, Mühleisen TW, Möhlenkamp S, Horsthemke B, Boes T, Bröcker-Preuss M, Mann K, Erbel R, Jöckel KH, Nöthen MM, Moebus S (2010) Coronary artery calcification and its relationship to validated genetic variants for diabetes mellitus assessed in the Heinz Nixdorf recall cohort. Arterioscler Thromb Vasc Biol 30:1867–1872.  https://doi.org/10.1161/ATVBAHA.110.208496CrossRefGoogle Scholar
  123. Petchey LK, Risebro CA, Vieira JM, Roberts T, Bryson JB, Greensmith L, Lythgoe MF, Riley PR (2014) Loss of Prox1 in striated muscle causes slow to fast skeletal muscle fiber conversion and dilated cardiomyopathy. Proc Natl Acad Sci U S A 111:9515–9520.  https://doi.org/10.1073/pnas.1406191111CrossRefGoogle Scholar
  124. Powers SE, Taniguchi K, Yen W, Melhuish TA, Shen J, Walsh CA, Sutherland AE, Wotton D (2010) Tgif1 and Tgif2 regulate Nodal signaling and are required for gastrulation. Development 137:249–259.  https://doi.org/10.1242/dev.040782CrossRefGoogle Scholar
  125. Pradhan L, Gopal S, Li S, Ashur S, Suryanarayanan S, Kasahara H, Nam H (2016) Intermolecular interactions of cardiac transcription factors NKX2.5 and TBX5. Biochemistry 55:1702–1710.  https://doi.org/10.1021/acs.biochem.6b00171CrossRefGoogle Scholar
  126. Prall OW, Menon MK, Solloway MJ, Watanabe Y, Zaffran S, Bajolle F, Biben C, McBride JJ, Robertson BR, Chaulet H, Stennard FA, Wise N, Schaft D, Wolstein O, Furtado MB, Shiratori H, Chien KR, Hamada H, Black BL, Saga Y, Robertson EJ, Buckingham ME, Harvey RP (2007) An Nkx2-5/Bmp2/Smad1 negative feedback loop controls heart progenitor specification and proliferation. Cell 128:947–959Google Scholar
  127. Puskaric S, Schmitteckert S, Mori AD, Glaser A, Schneider KU, Bruneau BG, Blaschke RJ, Steinbeisser H, Rappold G (2010) Shox2 mediates Tbx5 activity by regulating Bmp4 in the pacemaker region of the developing heart. Hum Mol Genet 19:4625–4633.  https://doi.org/10.1093/hmg/ddq393CrossRefGoogle Scholar
  128. Ragvin A, Moro E, Fredman D, Navratilova P, Drivenes Ø, Engström PG, Alonso ME, de la Calle Mustienes E, Gómez Skarmeta JL, Tavares MJ, Casares F, Manzanares M, van Heyningen V, Molven A, Njølstad PR, Argenton F, Lenhard B, Becker TS (2010) Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX, SOX4, and IRX3. Proc Natl Acad Sci U S A 107:775–780.  https://doi.org/10.1073/pnas.0911591107CrossRefGoogle Scholar
  129. Reamon-Buettner SM, Hecker H, Spanel-Borowski K, Craatz S, Kuenzel E, Borlak J (2004) Novel NKX2-5 mutations in diseased heart tissues of patients with cardiac malformations. Am J Pathol 164:2117–2125.  https://doi.org/10.1016/S0002-9440(10)63770-4CrossRefGoogle Scholar
  130. Risebro CA, Searles RG, Melville A, Athalie AD et al (2009) Prox1 maintains muscle structure and growth in the developing heart. Development 136:495–505.  https://doi.org/10.1242/dev.030007CrossRefGoogle Scholar
  131. Risebro CA, Petchey LK, Smart N et al (2012) Epistatic rescue of Nkx2.5 adult cardiac conduction disease phenotypes by prospero-related homeobox protein 1 and HDAC3. Circ Res 111:e19-31.  https://doi.org/10.1161/CIRCRESAHA.111.260695CrossRefGoogle Scholar
  132. Roux M, Laforest B, Capecchi M, Bertrand N, Zaffran S (2015) Hoxb1 regulates proliferation and differentiation of second heart field progenitors in pharyngeal mesoderm and genetically interacts with Hoxa1 during cardiac outflow tract development. Dev Biol 406:247–258.  https://doi.org/10.1016/j.ydbio.2015.08.015CrossRefGoogle Scholar
  133. Santini MP, Forte E, Harvey RP, Kovacic JC (2016) Developmental origin and lineage plasticity of endogenous cardiac stem cells. Development 4:1242–1258.  https://doi.org/10.1242/dev.111591CrossRefGoogle Scholar
  134. Schäfer K, Neuhaus P, Kruse J, Braun T (2003) The homeobox gene Lbx1 specifies a subpopulation of cardiac neural crest necessary for normal heart development. Circ Res 92:73–80Google Scholar
  135. Schneider MD, Baker AH, Riley P (2015) Hopx and the cardiomyocyte parentage. Mol Ther 23:1420–1422.  https://doi.org/10.1038/mt.2015.140CrossRefGoogle Scholar
  136. Schwab K, Hartman HA, Liang HC, Aronow BJ, Patterson LT, Potter SS (2006) Comprehensive microarray analysis of hoxa11/hoxd11 mutant kidney development. Dev Biol 293:540–554.  https://doi.org/10.1016/j.ydbio.2006.02.023CrossRefGoogle Scholar
  137. Seifert A, Werheid DF, Knapp SM, Tobiasch E (2015) Role of Hox genes in stem cell differentiation. World J Stem Cells 7:583–595.  https://doi.org/10.4252/wjsc.v7.i3.583CrossRefGoogle Scholar
  138. Sepulveda JL, Belaguli N, Nigam V, Chen CY, Nemer M, Schwartz RJ (1998) GATA-4 and Nkx-2.5 coactivate Nkx-2 DNA binding targets: role for regulating early cardiac gene expression. Mol Cell Biol 18:3405–3415Google Scholar
  139. Shashikant CS, Utset MF, Violette SM, Wise TL, Einat P, Einat MPJ, Schughart K, Ruddle FH (1991) Homeobox genes in mouse development. Crit Rev Eukaryot Gene Expr 1:207–245Google Scholar
  140. Shiratori H, Yashiro K, Shen MM, Hamada H (2006) Conserved regulation and role of Pitx2 in situs-specific morphogenesis of visceral organs. Development 133:3015–3025.  https://doi.org/10.1242/dev.02470CrossRefGoogle Scholar
  141. Skerjanc IS, Petropoulos H, Ridgeway AG, Wilton S (1998) Myocyte enhancer factor 2C and Nkx2-5 up-regulate each other’s expression and initiate cardiomyogenesis in P19 cells. J Biol Chem 273:34904–34910.  https://doi.org/10.1074/jbc.273.52.34904CrossRefGoogle Scholar
  142. Smith JG, Newton-Cheh C (2015) Genome-wide association studies of late-onset cardiovascular disease. J Mol Cell Cardiol 83:131–141.  https://doi.org/10.1016/j.yjmcc.2015.04.004CrossRefGoogle Scholar
  143. Soibam B, Benham A, Kim J, Weng KC, Yang L, Xu X, Robertson M, Azares A, Cooney AJ, Schwartz RJ, Liu Y (2015) Genome-wide identification of MESP1 targets demonstrates primary regulation over. Stem Cells 33:3254–3265.  https://doi.org/10.1002/stem.2111CrossRefGoogle Scholar
  144. Stankunas K, Shang C, Twu KY, Kao SC, Jenkins NA, Copeland NG, Sanyal M, Selleri L, Cleary ML, Chang C (2008) Pbx/Meis deficiencies demonstrate multigenetic origins of congenital heart disease. Circ Res 103:702–709.  https://doi.org/10.1161/CIRCRESAHA.108.175489CrossRefGoogle Scholar
  145. Stevens KN, Hakonarson H, Kim CE, Doevendans PA, Koeleman BP, Mital S, Raue J, Glessner JT, Coles JG, Moreno V, Granger A, Gruber SB, Gruber PJ (2010) Common variation in ISL1 confers genetic susceptibility for human congenital heart disease. PLoS One 26:e10855.  https://doi.org/10.1371/journal.pone.0010855CrossRefGoogle Scholar
  146. Sun R, Liu M, Lu L, Zheng Y, Zhang P (2015) Congenital heart disease: causes, diagnosis, symptoms, and treatments. Cell Biochem Biophys 72:857–860.  https://doi.org/10.1007/s12013-015-0551-6CrossRefGoogle Scholar
  147. Tanaka M, Chen Z, Bartunkova S, Yamasaki N, Izumo S (1999) The cardiac homeobox gene Csx/Nkx2.5 lies genetically upstream of multiple genes essential for heart development. Development 126:1269–1280Google Scholar
  148. Tanaka M, Yamasaki N, Izumo S (2000) Phenotypic characterization of the murine Nkx2.6 homeobox gene by gene targeting. Mol Cell Biol 20:2874–2879Google Scholar
  149. Trivedi CM, Zhu W, Wang Q et al (2010) Hopx and Hdac2 interact to modulate Gata4 acetylation and embryonic cardiac myocyte proliferation. Dev Cell 19:450–459.  https://doi.org/10.1016/j.devcel.2010.08.012CrossRefGoogle Scholar
  150. Trivedi CM, Cappola TP, Margulies KB, Epstein JA (2011) Homeodomain only protein x is down-regulated in human heart failure. J Mol Cell Cardiol 50:1056–1058.  https://doi.org/10.1021/nl061786n.Core-ShellCrossRefGoogle Scholar
  151. Tu CT, Yang TC, Tsai HJ (2009) Nkx2.7 and Nkx2.5 function redundantly and are required for cardiac morphogenesis of zebrafish embryos. PLoS One 4:e4249.  https://doi.org/10.1371/journal.pone.0004249CrossRefGoogle Scholar
  152. van der Harst P, van Setten J, Verweij N, Vogler G, Franke L, Maurano MT, Wang X, Mateo Leach I, Eijgelsheim M, Sotoodehnia N, Hayward C, Sorice R, Meirelles O, Lyytikäinen LP, Polašek O, Tanaka T, Arking DE, Ulivi S, Trompet S et al (2016) 52 genetic loci influencing myocardial mass. J Am Coll Cardiol 68:1435–1448.  https://doi.org/10.1016/j.jacc.2016.07.729CrossRefGoogle Scholar
  153. van Tuyl M, Liu J, Groenman F, Ridsdale R, Han RN, Venkatesh V, Tibboel D, Post M (2006) Iroquois genes influence proximo-distal morphogenesis during rat lung development. Am J Physiol Lung Cell Mol Physiol 290:L777–L789.  https://doi.org/10.1152/ajplung.00293.2005CrossRefGoogle Scholar
  154. van Weerd JH, Christoffels VM (2016) The formation and function of the cardiac conduction system. Development 143:197–210.  https://doi.org/10.1242/dev.124883CrossRefGoogle Scholar
  155. Vandewalle C, Van Roy F, Berx G (2009) The role of the ZEB family of transcription factors in development and disease. Cell Mol Life Sci 66:773–787.  https://doi.org/10.1007/s00018-008-8465-8CrossRefGoogle Scholar
  156. Wang J, Klysik E, Sood S, Johnson RL, Wehrens XH, Martin JF (2010) Pitx2 prevents susceptibility to atrial arrhythmias by inhibiting left-sided pacemaker specification. Proc Natl Acad Sci U S A 107:9753–9758.  https://doi.org/10.1073/pnas.0912585107CrossRefGoogle Scholar
  157. Wang J, Greene SB, Martin JF (2011) BMP signaling in congenital heart disease: new developments and future directions. Birth Defects Res A Clin Mol Teratol 91:441–448.  https://doi.org/10.1002/bdra.20785CrossRefGoogle Scholar
  158. Wang J, Xin YF, Xu WJ, Liu ZM, Qiu XB, Qu XK, Xu L, Li X, Yang Y (2013) Prevalence and spectrum of PITX2c mutations associated with congenital heart disease. DNA Cell Biol 32:708–716.  https://doi.org/10.1089/dna.2013.2185CrossRefGoogle Scholar
  159. Wang J, Zhang DF, Sun YM, Li RG, Qiu XB, Qu XK, Liu X, Fang WY, Yang YQ (2014) NKX2-6 mutation predisposes to familial atrial fibrillation. Int J Mol Med 34:1581–1590.  https://doi.org/10.3892/ijmm.2014.1971CrossRefGoogle Scholar
  160. Wang Y, Li Y, Guo C, Lu Q, Wang W, Jia Z, Chen P, Ma K, Reinberg D, Zhou C (2016) ISL1 and JMJD3 synergistically control cardiac differentiation of embryonic stem cells. Nucl Acids Res 44:6741–6755.  https://doi.org/10.1093/nar/gkw301CrossRefGoogle Scholar
  161. Waraya M, Yamashita K, Katoh H, Ooki A, Kawamata H, Nishimiya HNK, Ema A, Watanabe M (2012) Cancer specific promoter CpG Islands hypermethylation of HOP homeobox (HOPX) gene and its potential tumor suppressive role in pancreatic carcinogenesis. BMC Cancer 12:397.  https://doi.org/10.1186/1471-2407-12-397CrossRefGoogle Scholar
  162. Wei D, Gong XH, Qiu G, Wang J, Yang Y (2014) Novel PITX2c loss-of-function mutations associated with complex congenital heart disease. Int J Mol Med 33:1201–1208.  https://doi.org/10.3892/ijmm.2014.1689CrossRefGoogle Scholar
  163. Witzel HR, Jungblut B, Choe CP, Crump JG, Braun T, Crump JG (2012) The LIM protein Ajuba restricts the second heart field progenitor pool by regulating Isl1 activity. Dev Cell 23:58–70.  https://doi.org/10.1016/j.devcel.2012.06.005CrossRefGoogle Scholar
  164. Wu YH, Zhao H, Zhou LP, Zhao CX, Wu YF, Zhen LX, Li J, Ge DX, Xu L, Lin L, Liu Y, Liang DD, Chen Y (2015) miR-134 modulates the proliferation of human cardiomyocyte progenitor cells by targeting Meis2. Int J Mol Sci 6224:25199–25213.  https://doi.org/10.3390/ijms161025199CrossRefGoogle Scholar
  165. Xu H, Baldini A (2007) Genetic pathways to mammalian heart development: recent progress from manipulation of the mouse genome. Semin Cell Dev Biol 18:77–83.  https://doi.org/10.1016/j.semcdb.2006.11.011CrossRefGoogle Scholar
  166. Xu H, Yi Q, Yang C, Wang Y, Tian J, Zhu J (2016) Histone modifications interact with DNA methylation at the GATA4 promoter during differentiation of mesenchymal stem cells into cardiomyocyte-like cells. Cell Prolif 49:315–329.  https://doi.org/10.1111/cpr.12253CrossRefGoogle Scholar
  167. Yamagishi H, Yamagishi C, Nakagawa O, Harvey RP, Olson EN, Srivastava D (2001) The combinatorial activities of Nkx2.5 and dHAND are essential for cardiac ventricle formation. Dev Biol 239:190–203.  https://doi.org/10.1006/dbio.2001.0417CrossRefGoogle Scholar
  168. Yap LF, Lai SL, Patmanathan SN et al (2016) HOPX functions as a tumour suppressor in head and neck cancer. Sci Rep 6:38758.  https://doi.org/10.1038/srep38758CrossRefGoogle Scholar
  169. Yousef MS, Matthews BW (2005) Structural basis of Prospero-DNA interaction: implications for transcription regulation in developing cells. Structure 13:601–607.  https://doi.org/10.1016/j.str.2005.01.023CrossRefGoogle Scholar
  170. Yu X, St Amand TR, Wang S, Li G, Zhang Y, Hu YP, Nguyen L, Qiu MS, Chen Y (2001) Differential expression and functional analysis of Pitx2 isoforms in regulation of heart looping in the chick. Development 1013:1005–1013Google Scholar
  171. Yu Z, Kong J, Pan B, Sun H, Lv T, Zhu J, Huang G, Tian J (2013) Islet-1 may function as an assistant factor for histone acetylation and regulation of cardiac development-related transcription factor Mef2c expression. PLoS One 8:e77690.  https://doi.org/10.1371/journal.pone.0077690CrossRefGoogle Scholar
  172. Zakariyah AF, Rajgara RF, Veinot JP, Skerjanc IS, Burgon PG (2017) Congenital heart defect causing mutation in Nkx2.5 displays in vivo functional deficit. J Mol Cell Cardiol 105:89–98.  https://doi.org/10.1016/j.yjmcc.2017.03.003CrossRefGoogle Scholar
  173. Zhang SS, Kim KH, Rosen A, Smyth JW, Sakuma R, Delgado-Olguín P, Davis M, Chi NC, Puviindran V, Gaborit N, Sukonnik T, Wylie JN, Brand-Arzamendi K, Farman GP, Kim J, Rose RA, Marsden PA, Zhu Y, Zhou YQ, Miquerol L, Henkelman RM, Stainier DY, Shaw RM, Hui CC, Bruneau BG, Backx PH (2011) Iroquois homeobox gene 3 establishes fast conduction in the cardiac His-Purkinje network. Proc Natl Acad Sci U S A 108:13576–13581.  https://doi.org/10.1073/pnas.1106911108CrossRefGoogle Scholar
  174. Zhang Y, Si Y, Ma N, Mei J (2015) The RNA-binding protein PCBP2 inhibits Ang II-induced hypertrophy of cardiomyocytes though promoting GPR56 mRNA degeneration. Biochem Biophys Res Commun 464:679–684.  https://doi.org/10.1016/j.bbrc.2015.06.139CrossRefGoogle Scholar
  175. Zhang Y, Si Y, Ma N (2016) Meis1 promotes poly (rC)-binding protein 2 expression and inhibits angiotensin II-induced cardiomyocyte hypertrophy. IUBMB Life 68:13–22.  https://doi.org/10.1002/iub.1456CrossRefGoogle Scholar
  176. Zhou Z, Wang J, Guo C, Chang W, Zhuang J, Zhu P, Li X (2017) Temporally distinct Six2-positive second heart field progenitors regulate mammalian heart development and disease. Cell Rep 18:1019–1032.  https://doi.org/10.1016/j.celrep.2017.01.002CrossRefGoogle Scholar
  177. Zhu CC, Yamada G, Nakamura S, Terashi T, Schweickert A, Blum M (1998) Malformation of trachea and pelvic region in goosecoid mutant mice. Dev Dyn 211:374–381.  https://doi.org/10.1002/(SICI)1097-0177(199804)211:4<374::AID-AJA8>3.0.CO;2-ECrossRefGoogle Scholar
  178. Zhuang S, Zhang Q, Zhuang T, Evans SM, Liang X, Sun Y (2013) Expression of Isl1 during mouse development. Gene Expr Patterns 13:407–412.  https://doi.org/10.1016/j.gep.2013.07.001.ExpressionCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Rokas Miksiunas
    • 1
  • Ali Mobasheri
    • 1
  • Daiva Bironaite
    • 1
    Email author
  1. 1.Department of Regenerative MedicineState Research Institute Centre for Innovative MedicineVilniusLithuania

Personalised recommendations