Homeobox transcription factor Pitx2: The rise of an asymmetry gene in cardiogenesis and arrhythmogenesis

Trends in Cardiovascular Medicine

Volumn 24, Issue 1, 2014, Pages 23-31

  Franco, Diego ^a   Christoffels, Vincent M ^b   Campione, Marina ^c  

^a UNIVERSITY OF JAÉN   (Spain)

^b ACADEMIC MEDICAL CENTER   (Netherlands)

^c UNIVERSITY OF PADOVA   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

TRANSCRIPTION FACTOR PITX2;

ARRHYTHMOGENESIS; GENE; GENE EXPRESSION; GENE STRUCTURE; GENE TARGETING; HEART ATRIUM ARRHYTHMIA; HEART DEVELOPMENT; HEART MUSCLE CONDUCTION SYSTEM; HUMAN; NONHUMAN; PITX2 GENE; PRIORITY JOURNAL; REVIEW; TRANSCRIPTION REGULATION;

ANIMALS; ARRHYTHMIAS, CARDIAC; GENE EXPRESSION REGULATION, DEVELOPMENTAL; GENETIC PREDISPOSITION TO DISEASE; HEART; HOMEODOMAIN PROTEINS; HUMANS; MICE; MICE, KNOCKOUT; MORPHOGENESIS; MYOCARDIUM; PHENOTYPE; SIGNAL TRANSDUCTION; TRANSCRIPTION FACTORS; TRANSCRIPTION, GENETIC;

EID: 84890798504     PISSN: 10501738     EISSN: 18732615     Source Type: Journal    
DOI: 10.1016/j.tcm.2013.06.001     Document Type: Review

References (73)

1. Ai D., Liu W., Ma L., Dong F., Lu M.F., Wang D., et al. Pitx2 regulates cardiac left-right asymmetry by patterning second cardiac lineage-derived myocardium. Developmental Biology 2006, 296:437-449.
2. Ammirabile G., Tessari A., Pignataro V., Szumska D., Sutera Sardo F., Benes J., et al. Pitx2 confers left morphological, molecular, and functional identity to the sinus venosus myocardium. Cardiovascular Research 2012, 93:291-301.
3. Bajolle F., Zaffran S., Kelly R.G., Hadchouel J., Bonnet D., Brown N.A., et al. Rotation of the myocardial wall of the outflow tract is implicated in the normal positioning of the great arteries. Circulation Research 2006, 98:421-428.
4. Bamforth S.D., Bragança J., Farthing C.R., Schneider J.E., Broadbent C., Michell A.C., et al. Cited2 controls left-right patterning and heart development through a Nodal-Pitx2c pathway. Nature Genetics 2004, 36:1189-1196.
5. Bisgrove B.W., Essner J.J., Yost H.J. Multiple pathways in the midline regulate concordant brain, heart and gut left-right asymmetry. Development 2000, 127:3567-3579.
6. Boorman C.J., Shimeld S.M. The evolution of left-right asymmetry in chordates. Bioessays 2002, 24(11):1004-1011.
7. Campione M., Ros M.A., Icardo J.M., Piedra E., Christoffels V.M., Schweickert A., et al. Pitx2 expression defines a left cardiac lineage of cells: evidence for atrial and ventricular molecular isomerism in the iv/iv mice. Developmental Biology 2001, 231:252-264.
8. Campione M., Steinbeisser H., Schweickert A., Deissler K., van Bebber F., Lowe L.A., et al. The homeobox gene Pitx2: mediator of asymmetric left-right signaling in vertebrate heart and gut looping. Development 1999, 126:1225-1234.
9. Chang T.C., Summers C.G., Schimmenti L.A., Grajewski A.L. Axenfeld-Rieger syndrome: new perspectives. British Journal of Ophthalmology 2012, 96:318-322.
10. Chinchilla A., Daimi H., Lozano-Velasco E., Dominguez J.N., Caballero R., Delpón E., et al. PITX2 insufficiency leads to atrial electrical and structural remodeling linked to arrhythmogenesis. Circulation Cardiovascular Genetics 2011, 4:269-279.
11. Christiaen L., Bourrat F., Joly J.S. A modular cis-regulatory system controls isoform-specific pitx expression in ascidian stomodaeum. Developmental Biology 2005, 277:557-566.
12. Christoffels V.M., Habets P.E., Franco D., Campione M., de Jong F., Lamers W.H., et al. Chamber formation and morphogenesis in the developing mammalian heart. Developmental Biology 2000, 223:266-278.
13. Christoffels V.M., Mommersteeg M.T., Trowe M.O., Prall O.W., de Gier-de Vries C., Soufan A.T., et al. Formation of the venous pole of the heart from an Nkx2-5-negative precursor population requires Tbx18. Circulation Research 2006, 98:1555-1563.
14. Cox C.J., Espinoza H.M., McWilliams B., Chappell K., Morton L., Hjalt T.A., et al. Differential regulation of gene expression by PITX2 isoforms. Journal of Biological Chemistry 2002, 277:25001-25010.
15. Cunningham E.T., Eliott D., Miller N.R., Maumenee I.H., Green W.R. Familial Axenfeld-Rieger anomaly, atrial septal defect, and sensorineural hearing loss: a possible new genetic syndrome. Archives of Ophthalmology 1998, 116:78-82.
16. Domínguez J.N., Meilhac S.M., Bland Y.S., Buckingham M.E., Brown N.A. Asymmetric fate of the posterior part of the second heart field results in unexpected left-right contributions to both poles of the heart. Circulation Research 2012, 111:1323-1335.
17. Ellinor P.T., Lunetta K.L., Albert C.M., Glazer N.L., Ritchie M.D., Smith A.V., et al. Meta-analysis identifies six new susceptibility loci for atrial fibrillation. Nature Genetics 2012, 44:670-675.
18. Franco D., Campione M., Kelly R., Zammit P.S., Buckingham M., Lamers W.H., et al. Multiple transcriptional domains, with distinct left and right components, in the atrial chambers of the developing heart. Circulation Research 2000, 87:984-991.
19. Furtado M.B., Biben C., Shiratori H., Hamada H., Harvey R.P. Characterization of Pitx2c expression in the mouse heart using a reporter transgene. Developmental Dynamics 2011, 240:195-203.
20. Gage P.J., Suh H., Camper S.A. Dosage requirement of Pitx2 for development of multiple organs. Development 1999, 126:4643-4651.
21. Galli D., Domínguez J.N., Zaffran S., Munk A., Brown N.A., Buckingham M.E. Atrial myocardium derives from the posterior region of the second heart field, which acquires left-right identity as Pitx2c is expressed. Development 2008, 135:1157-1167.
22. Ganga M., Espinoza H.M., Cox C.J., Morton L., Hjalt T.A., Lee Y., et al. PITX2 isoform-specific regulation of atrial natriuretic factor expression: synergism and repression with Nkx2.5. Journal of Biological Chemistry 2003, 278:22437-22445.
23. Gormley J.P., Nascone-Yoder N.M. Left and right contributions to the Xenopus heart: implication for asymmetric morphogenesis. Development Genes and Evolution 2003, 213:390-398.
24. Grote P., Wittler L., Hendrix D., Koch F., Währisch S., Beisaw A., et al. The tissue-specific lncRNA Fendrr is an essential regulator of heart and body wall development in the mouse. Developmental Cell 2013, 24:206-214.
25. Gudbjartsson D.F., Arnar D.O., Helgadottir A., Gretarsdottir S., Holm H., Sigurdsson A., et al. Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature 2007, 448:353-357.
26. Guioli S., Lovell-Badge R. PITX2 controls asymmetric gonadal development in both sexes of the chick and can rescue the degeneration of the right ovary. Development 2007, 134:4199-4208.
27. Husser D., Adams V., Piorkowski C., Hindricks G., Bollmann A. Chromosome 4q25 variants and atrial fibrillation recurrence after catheter ablation. Journal of the American College of Cardiology 2010, 55:747-753.
28. Jensen B., Wang T., Christoffels V.M., Moorman A.F. Evolution and development of the building plan of the vertebrate heart. Biochimica et Biophysica Acta 2013, 1833(4):783-794.
29. Kahr P.C., Piccini I., Fabritz L., Greber B., Schöler H., Scheld H.H., et al. Systematic analysis of gene expression differences between left and right atria in different mouse strains and in human atrial tissue. PLoS One 2011, 6:e26389.
30. Kelly R.G. The second heart field. Current Topics in Developmental Biology 2012, 100:33-65.
31. Kirchhof P., Kahr P.C., Kaese S., Piccini I., Vokshi I., Scheld H.H., et al. PITX2c is expressed in the adult left atrium, and reducing Pitx2c expression promotes atrial fibrillation inducibility and complex changes in gene expression. Circulation Cardiovascular Genetics 2011, 4:123-133.
32. Kitamura K., Miura H., Miyagawa-Tomita S., Yanazawa M., Katoh-Fukui Y., Suzuki R., et al. Mouse Pitx2 deficiency leads to anomalies of the ventral body wall, heart, extra- and periocular mesoderm and right pulmonary isomerism. Development 1999, 126:5749-5758.
33. Kreiling J.A., Balantac Z.L., Crawford A.R., Ren Y., Toure J., Zchut S., et al. Suppression of the endoplasmic reticulum calcium pump during zebrafish gastrulation affects left-right asymmetry of the heart and brain. Mechanics of Development 2008, 125:396-410.
34. Levin M., Palmer A.R. Left-right patterning from the inside out: widespread evidence for intracellular control. Bioessays 2007, 29:271-287.
35. Lin C.R., Kioussi C., O'Connell S., Briata P., Szeto D., Liu F., et al. Pitx2 regulates lung asymmetry, cardiac positioning and pituitary and tooth morphogenesis. Nature 1999, 401:279-282.
36. Linask K.K., Yu X., Chen Y., Han M.D. Directionality of heart looping: effects of Pitx2c misexpression on flectin asymmetry and midline structures. Developmental Biology 2002, 246:407-417.
37. Liu C., Liu W., Palie J., Lu M.F., Brown N.A., Martin J.F. Pitx2c patterns anterior myocardium and aortic arch vessels and is required for local cell movement into atrioventricular cushions. Development 2002, 129:5081-5091.
38. Liu C., Liu W., Lu M.F., Brown N.A., Martin JF. Regulation of left-right asymmetry by thresholds of Pitx2c activity. Development 2001, 128:2039-2048.
39. Lu M.F., Pressman C., Dyer R., Johnson R.L., Martin JF. Function of Rieger syndrome gene in left-right asymmetry and craniofacial development. Nature 1999, 401:276-278.
40. Lozano-Velasco E., Chinchilla A., Martínez-Fernández S., Hernández-Torres F., Navarro F., Lyons G.E., et al. Pitx2c modulates cardiac-specific transcription factors networks in differentiating cardiomyocytes from murine embryonic stem cells. Cells Tissues Organs 2011, 194:49-62.
41. Ma H.Y., Xu J., Eng D., Gross M.K., Kioussi C. Pitx2-mediated cardiac outflow tract remodeling. Developmental Dynamics 2013, 10.1002/dvdy.23934.
42. Mammi I., De Giorgio P., Clementi M., Tenconi R. Cardiovascular anomaly in Rieger syndrome: heterogeneity or contiguity?. Acta Ophthalmologica Scandinavica 1998, 76:509-512.
43. Martin D.M., Probst F.J., Fox S.E., Schimmenti L.A., Semina E.V., Hefner M.A., et al. Exclusion of PITX2 mutations as a major cause of CHARGE association. American Journal of Medical Genetics 2002, 111:27-30.
44. Martin D.M., Skidmore J.M., Philips S.T., Vieira C., Gage P.J., Condie B.G., et al. PITX2 is required for normal development of neurons in the mouse subthalamic nucleus and midbrain. Developmental Biology 2004, 267:93-108.
45. Miquerol L., Bellon A., Moreno N., Beyer S., Meilhac S.M., Buckingham M., et al. Resolving cell lineage contributions to the ventricular conduction system with a Cx40-GFP allele: a dual contribution of the first and second heart fields. Developmental Dynamics 2013, 10.1002/dvdy.23964.
46. Mommersteeg M.T., Brown N.A., Prall O.W., de Gier-de Vries C., Harvey R.P., Moorman A.F., et al. Pitx2c and Nkx2-5 are required for the formation and identity of the pulmonary myocardium. Circulation Research 2007, 101:902-909.
47. Mommersteeg M.T., Domínguez J.N., Wiese C., Norden J., de Gier-de Vries C., Burch J.B., Kispert A., Brown N.A., Moorman A.F., Christoffels VM. The sinus venosus progenitors separate and diversify from the first and second heart fields early in development. Cardiovasc Res 2010, 87:92-101.
48. Moorman A.F., Christoffels V.M. Cardiac chamber formation: development, genes, and evolution. Physiological Reviews 2003, 83:1223-1267.
49. Muncke N., Niesler B., Roeth R., Schön K., Rüdiger H.J., Goldmuntz E., et al. Mutational analysis of the PITX2 coding region revealed no common cause for transposition of the great arteries (dTGA). BMC Medical Genetics 2005, 6:20.
50. Nakamura T., Hamada H. Left-right patterning: conserved and divergent mechanisms. Development 2012, 139:3257-3262.
51. Nowotschin S., Liao J., Gage P.J., Epstein J.A., Campione M., Morrow B.E. Tbx1 affects asymmetric cardiac morphogenesis by regulating Pitx2 in the secondary heart field. Development 2006, 133:1565-1573.
52. Parvez B., Benjamin Shoemaker M., Muhammad R., Richardson R., Jiang L., Blair M.A., et al. Common genetic polymorphism at 4q25 locus predicts atrial fibrillation recurrence after successful cardioversion. Heart Rhythm 2013, 10:849-855.
53. Piedra M.E., Icardo J.M., Albajar M., Rodriguez-Rey J.C., Ros M.A. Pitx2 participates in the late phase of the pathway controlling left-right asymmetry. Cell 1998, 94:319-324.
54. Saxena A., Tabin C.J. miRNA-processing enzyme Dicer is necessary for cardiac outflow tract alignment and chamber septation. Proceedings of the National Academy of Sciences of the United States of America 2010, 107:87-91.
55. Schulte I., Schlueter J., Abu-Issa R., Brand T., Männer J. Morphological and molecular left-right asymmetries in the development of the proepicardium: a comparative analysis on mouse and chick embryos. Developmental Dynamics 2007, 236:684-695.
56. Schweickert A., Campione1 M., Steinbeisser H., Blum M. Pitx2 isoforms: involvement of Pitx2c but not Pitx2a or Pitx2b in vertebrate left-right asymmetry. Mechanics of Development 2000, 90:41-51.
57. Semina E.V., Reiter R., Leysens N.J., Alward W.L.M., Small K.W., Datson N.A., et al. Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome. Nature Genetics 1996, 14:392-399.
58. Shiratori H., Hamada H. The left-right axis in the mouse: from origin to morphology. Development 2006, 133:2095-2104.
59. Shiratori H., Yashiro K., Shen M.M., Hamada H. Conserved regulation and role of Pitx2 in situs-specific morphogenesis of visceral organs. Development 2006, 133:3015-3025.
60. Shiratori H., Sakuma R., Watanabe M., Hashiguchi H., Mochida K., Sakai Y., et al. Two-step regulation of left-right asymmetric expression of Pitx2: initiation by nodal signaling and maintenance by Nkx2. Molecules and Cells 2001, 7:137-149.
61. Sinner M.F., Ellinor P.T., Meitinger T., Benjamin E.J., Kääb S. Genome-wide association studies of atrial fibrillation: past, present, and future. Cardiovascular Research 2011, 89:701-709.
62. Sun Y., Yang Y.Q., Gong X.Q., Wang X.H., Li R.G., Tan H.W., et al. Novel germline GJA5/connexin40 mutations associated with lone atrial fibrillation impair gap junctional intercellular communication. Human Mutation 2013, 10.1002/humu.22278.
63. Tessari A., Pietrobon M., Notte A., Cifelli G., Gage P.J., Schneider M.D., et al. Myocardial Pitx2 differentially regulates the left atrial identity and ventricular asymmetric remodeling programs. Circulation Research 2008, 102:813-822.
64. Toro R., Saadi I., Kuburas A., Nemer M., Russo A.F. Cell-specific activation of the atrial natriuretic factor promoter by PITX2 and MEF2A. Journal of Biological Chemistry 2004, 279:52087-52094.
65. Tsai J.C., Grajewski A.L. Cardiac valvular disease and Axenfeld-Rieger syndrome. American Journal of Ophthalmology 1994, 118:255-256.
66. Vandenberg L.N., Levin M. A unified model for left-right asymmetry? Comparison and synthesis of molecular models of embryonic laterality. Developmental Biology 2013, [Epub ahead of print].
67. Vandenberg L.N., Levin M. Far from solved: a perspective on what we know about early mechanisms of left-right asymmetry. Developmental Dynamics 2010, 239:3131-3146.
68. Wang J., Klysik E., Sood S., Johnson R.L., Wehrens X.H., Martin J.F. Pitx2 prevents susceptibility to atrial arrhythmias by inhibiting left-sided pacemaker specification. Proceedings of the National Academy of Sciences of the United States of America 2010, 107:9753-9758.
69. Yashiro K., Shiratori H., Hamada H. Haemodynamics determined by a genetic programme govern asymmetric development of the aortic arch. Nature 2007, 450:285-288.
70. Yeh Y.H., Kuo C.T., Lee Y.S., Lin Y.M., Nattel S., Tsai F.C., et al. Region-specific gene expression profiles in the left atria of patients with valvular atrial fibrillation. Heart Rhythm 2013, 10:383-391.
71. Zaidi S., Choi M., Wakimoto H., Ma L., Jiang J., Overton J.D., et al. De novo mutations in histone-modifying genes in congenital heart disease. Nature 2013, [Epub ahead of print]. 10.1038/nature12141.
72. Zhao Y., Ransom J.F., Li A., Vedantham V., von Drehle M., Muth A.N., et al. Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell 2007, 129:303-317.
73. Zhou W., Lin L., Majumdar A., Li X., Zhang X., Liu W., et al. Modulation of morphogenesis by noncanonical Wnt signaling requires ATF/CREB family-mediated transcriptional activation of TGFbeta2. Nature Genetics 2007, 39:1225-1234.