Tbx5specifies the left/right ventricles and ventricular septum position during cardiogenesis
10.1242/dev.00797
Crossref journal-article
The Company of Biologists
Development (237)
Abstract

Extensive misexpression studies were carried out to explore the roles played by Tbx5, the expression of which is excluded from the right ventricle (RV) during cardiogenesis. When Tbx5 was misexpressed ubiquitously,ventricular septum was not formed, resulting in a single ventricle. In such heart, left ventricle (LV)-specific ANF gene was induced. In search of the putative RV factor(s), we have found that chick Tbx20 is expressed in the RV, showing a complementary fashion to Tbx5. In the Tbx5-misexpressed heart, this gene was repressed. When misexpression was spatially partial, leaving small Tbx5-negative area in the right ventricle,ventricular septum was shifted rightwards, resulting in a small RV with an enlarged LV. Focal expression induced an ectopic boundary of Tbx5-positive and-negative regions in the right ventricle, at which an additional septum was formed. Similar results were obtained from the transient transgenic mice. In such hearts, expression patterns of dHAND and eHAND were changed with definitive cardiac abnormalities. Furthermore, we report that human ANF promoter is synergistically activated by Tbx5, Nkx2.5 and GATA4. This activation was abrogated by Tbx20, implicating the pivotal roles of interactions among these heart-specific factors. Taken together, our data indicate that Tbx5 specifies the identity of LV through tight interactions among several heart-specific factors, and highlight the essential roles of Tbx5 in cardiac development.

Bibliography

Takeuchi, J. K., Ohgi, M., Koshiba-Takeuchi, K., Shiratori, H., Sakaki, I., Ogura, K., Saijoh, Y., & Ogura, T. (2003). Tbx5specifies the left/right ventricles and ventricular septum position during cardiogenesis. Development, 130(24), 5953–5964.

Authors 8
  1. Jun K. Takeuchi (first)
  2. Makoto Ohgi (additional)
  3. Kazuko Koshiba-Takeuchi (additional)
  4. Hidetaka Shiratori (additional)
  5. Ichiro Sakaki (additional)
  6. Keiko Ogura (additional)
  7. Yukio Saijoh (additional)
  8. Toshihiko Ogura (additional)
References 63 Referenced 162
  1. Bamshad, M., Lin, R. C., Law, D. J., Watkins, W. C., Krakowiak,P. A., Moore, M. E., Franceschini, P., Lala, R., Holmes, L. B., Gebuhr,T. C. et al. (1997). Mutations in human TBX3 alter limb,apocrine and genital development in ulnar-mammary syndrome. Nat. Genet.16,311-315. (10.1038/ng0797-311)
  2. Basson, C. T., Bachinsky, D. R., Lin, R. C., Levi, T., Elkins,J. A., Soults, J., Grayzel, D., Kroumpouzou, E., Traill, T. A.,Leblanc-Straceski, J. et al. (1997). Mutations in human TBX5 cause limb and cardiac malformation in Holt-Oram syndrome. Nat. Genet.15,30-35. (10.1038/ng0197-30)
  3. Basson, C. T., Huang, T., Lin, R. C., Bachinsky, D. R.,Weremowicz, S., Vaglio, A., Bruzzone, R., Quadrelli, R., Lerone, M.,Romeo, G. et al. (1999). Different TBX5 interactions in heart and limb defined by Holt-Oram syndrome mutations. Proc. Natl. Acad. Sci. USA96,2919-2924. (10.1073/pnas.96.6.2919)
  4. Bruneau, B. G., Logan, M., Davis, N., Levi, T., Tabin, C. J.,Seidman, J. G. and Seidman, C. E. (1999). Chamber-specific cardiac expression of Tbx5 and heart defects in Holt-Oram syndrome. Dev. Biol. 211,100-108. (10.1006/dbio.1999.9298)
  5. Bruneau, B. G., Nemer, G., Schmitt, J. P., Charron, F.,Robitaille, L., Caron, S., Conner, D. A., Gessler, M., Nemer, M.,Seidman, C. E. and Seidman, J. G. (2001). A murine model of Holt-Oram syndrome defines roles of the T-box transcription factor Tbx5 in cardiogenesis and disease. Cell106,709-721. (10.1016/S0092-8674(01)00493-7)
  6. Bruneau, B. G. (2002). Transcriptional regulation of vertebrate cardiac morphogenesis. Circ. Res.90,509-519. (10.1161/01.RES.0000013072.51957.B7)
  7. Boussif, O., Lezoualch, F., Zanta, M. A., Mergny, M. D.,Scherman, D., Demeneix, B. and Behr, J. P. (1995). A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: Polyethylenimine. Proc. Natl. Acad. Sci. USA92,7297-7301. (10.1073/pnas.92.16.7297)
  8. Burnett, J. C., Jr, Kao, P. C., Hu, D. C., Heser, D. W.,Heublein, D., Granger, J. P., Opgenorth, T. J. and Reeder, G. S.(1986). Atrial natriuretic peptide elevation in congestive heart failure in the human. Science231,1145-1147. (10.1126/science.2935937)
  9. Chapman, D. L. and Papaioannou, V. E. (1998). Three neural tubes in mouse embryos with mutations in the T-box gene Tbx6. Nature391,695-697. (10.1038/35624)
  10. Clark, T. G., Conway, S. J., Scott, I. C., Labosky, P. A.,Winnier, G., Bundy, J., Hogan, B. L. and Greenspan, D. S.(1999). The mammalian Tolloid-like 1 gene, Tll1, is necessary for normal septation and positioning of the heart. Development126,2631-2642. (10.1242/dev.126.12.2631)
  11. Conlon, F. L., Fairclough, L., Price, B. M., Casey, E. S. and Smith, J. C. (2001). Determination of T box protein specificity. Development128,3749-3758.
  12. Durocher, D., Charron, F., Warren, R., Schwartz, R. J. and Nemer, M. (1997). The cardiac transcription factors Nkx2-5 and GATA-4 are mutual cofactors. EMBO J.16,5687-5696. (10.1093/emboj/16.18.5687)
  13. Epstein, J. A. (2001). Developing models of DiGeorge syndrome. Trends Genet.17, 13-17. (10.1016/S0168-9525(01)02450-7)
  14. Firulli, A. B., McFadden, D. G., Lin, Q., Srivastava, D. and Olson, E. N. (1998). Heart and extra-embryonic mesodermal defects in mouse embryos lacking the bHLH transcription factor Hand1. Nat. Genet. 18,266-270. (10.1038/ng0398-266)
  15. Fishman, M. C. and Chien, K. R. (1997). Fashioning the vertebrate heart: earliest embryonic decisions. Development124,2099-2117. (10.1242/dev.124.11.2099)
  16. Habets, P. E., Moorman, A. F., Clout, D. E., van Roon, M. A.,Lingbeek, M., van Lohuizen, M., Campione, M. and Christoffels, V. M. (2002). Cooperative action of Tbx2 and Nkx2.5 inhibits ANF expression in the atrioventricular canal: implications for cardiac chamber formation. Genes Dev.16,1234-1246.
  17. Hatcher, C. J. and Basson, C. T. (2001). Getting the T-box dose right. Nat. Med.7,1185-1186. (10.1038/nm1101-1185)
  18. Hatcher, C. J., Kim, M. S., Mah, C. S., Goldstein, M. M., Wong,B., Mikawa, T. and Basson, C. T. (2001). TBX5 transcription factor regulates cell proliferation during cardiogenesis. Dev. Biol.230,177-188. (10.1006/dbio.2000.0134)
  19. Hiroi, Y., Kudoh, S., Monzen, K., Ikeda, Y., Yazaki, Y., Nagai,R. and Komuro, I. (2001). Tbx5 associates with Nkx2.5 and synergistically promotes cardiomyocyte differentiation. Nat. Genet.28,276-280.
  20. Holt, M. and Oram, S. (1960). Familial heart disease with skeletal malformations. Br. Heart J.22,236-242. (10.1136/hrt.22.2.236)
  21. Horb, M. E. and Thomsen, G. H. (1999). Tbx5 is essential for heart development. Development126,1739-1751. (10.1242/dev.126.8.1739)
  22. Hsueh, Y. P., Wang, T. F., Yang, F. C. and Sheng, M.(2000). Nuclear translocation and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2. Nature404,298-302. (10.1038/35005118)
  23. Jerome, L. A. and Papaioannou, V. E. (2001). DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1. Nat. Genet27,286-291. (10.1038/85845)
  24. Kimura, S., Abe, K., Suzuki, M., Ogawa, M., Yoshioka, K.,Kaname, T., Miike, T. and Yamamura, K. (1997). A 900 bp genomic region from the mouse dystrophin promoter directs lacZ reporter expression only to the right heart of transgenic mice. Dev. Growth Differ.39,257-265. (10.1046/j.1440-169X.1997.t01-2-00001.x)
  25. Kispert, A. and Herrmann, B. G. (1993). The Brachyury gene encodes a novel DNA binding protein. EMBO J.12,3211-3220. (10.1002/j.1460-2075.1993.tb05990.x)
  26. Koshiba-Takeuchi, K., Takeuchi, J. K., Matsumoto, K., Momose,T., Uno, K., Hoepker, V., Ogura, K., Takahashi, N., Nakamura, H.,Yasuda, K. and Ogura, T. (2000). Tbx5 and the retinotectum projection. Science287,134-137. (10.1126/science.287.5450.134)
  27. Kraus, F., Haenig, B. and Kispert, A. (2001). Cloning and expression analysis of the mouse T-box gene Tbx20. Mech. Dev. 100,87-91. (10.1016/S0925-4773(00)00499-8)
  28. Kuisk, I. R., Li, H., Tran, D. and Capetanaki, Y.(1996) A single MEF2 site governs desmin transcription in both heart and skeletal muscle during mouse embryogenesis. Dev. Biol.174,1-13. (10.1006/dbio.1996.0046)
  29. Lee, Y., Shioi, T., Kasahara, H., Jobe, S. M., Wiese, R. J.,Markham, B. E. and Izumo, S. (1998). The cardiac tissue-restricted homeobox protein Csx/Nkx2.5 physically associates with the zinc finger protein GATA4 and cooperatively activates atrial natriuretic factor gene expression. Mol. Cell. Biol.18,3120-3129.
  30. Li, L., Miano, J. M., Mercer, B. and Olson, E. N.(1996) Expression of the SM22alpha promoter in transgenic mice provides evidence for distinct transcriptional regulatory programs in vascular and visceral smooth muscle cells. J. Cell Biol.132,849-859. (10.1083/jcb.132.5.849)
  31. Li, Q. Y., Newbury-Ecob, R. A., Terrett, J. A., Wilson, D. I.,Curtis, A. R., Yi, C. H., Gebuhr, T., Bullen, P. J., Robson, S. C.,Strachan, T. et al. (1997). Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family. Nat. Genet15,21-29. (10.1038/ng0197-21)
  32. Liberatore, C. M., Searcy-Schrick, R. D., and Yutzey, K. E.(2000). Ventricular expression of tbx5 inhibits normal heart chamber development. Dev. Biol.223,169-180. (10.1006/dbio.2000.9748)
  33. Lindsay, E. A., Vitelli, F., Su, H., Morishima, M., Huynh, T.,Pramparo, T., Jurecic, V., Ogunrinu, G., Sutherland, H. F., Scambler,P. J., Bradley, A. and Baldini, A. (2001). Tbx1 haploinsufficieny in the DiGeorge syndrome region causes aortic arch defects in mice. Nature410,97-101. (10.1038/35065105)
  34. Lyons, G. E., Schiaffino, S., Sassoon, D., Barton, P. and Buckingham, M. (1990a). Developmental regulation of myosin gene expression in mouse cardiac muscle. J. Cell Biol. 111,2427-2436. (10.1083/jcb.111.6.2427)
  35. Lyons, K. M., Pelton, R. W. and Hogan, B. L.(1990b). Organogenesis and pattern formation in the mouse: RNA distribution patterns suggest a role for bone morphogenetic protein-2A(BMP-2A). Development109,833-844. (10.1242/dev.109.4.833)
  36. Lyons, K. M., Hogan, B. L. and Robertson, E. J.(1995). Colocalization of BMP 7 and BMP 2 RNAs suggests that these factors cooperatively mediate tissue interactions during murine development. Mech. Dev.50, 71-83. (10.1016/0925-4773(94)00326-I)
  37. Merscher, S., Funke, B., Epstein, J. A., Heyer, J., Puech, A.,Lu, M. M., Xavier, R. J., Demay, M. B., Russell, R. G., Factor, S. et al. (2001). TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome. Cell104,619-629. (10.1016/S0092-8674(01)00247-1)
  38. Miquerol, L., Langille, B. L. and Nagy, A.(2000). Embryonic development is disrupted by modest increases in vascular endothelial growth factor gene expression. Development127,3941-3946. (10.1242/dev.127.18.3941)
  39. Moessler, H., Mericskay, M., Li, Z., Nagl, S., Paulin, D. and Small, J. V. (1996). The SM 22 promoter directs tissue-specific expression in arterial but not in venous or visceral smooth muscle cells in transgenic mice. Development122,2415-2425. (10.1242/dev.122.8.2415)
  40. Momose, T., Tonegawa, A., Takeuchi, J., Ogawa, H., Umesono, K. and Yasuda, K. (1999). Efficient targeting of gene expression in chick embryos by electroporation. Dev. Growth Differ.41,335-344. (10.1046/j.1440-169X.1999.413437.x)
  41. Montgomery, M. O., Litvin, J., Gonzalez-Sanchez. A. and Bader,D. (1994). Staging of commitment and differentiation of avian cardiac myocytes. Dev. Biol.164, 63-71. (10.1006/dbio.1994.1180)
  42. Motgan, B. A. and Fekete, D. M. (1996). Manipulating gene expression with replication-competent retroviruses. Methods Cell. Biol.51,185-218.
  43. Muller, C. and Herrmann, B. G. (1997). Crystallographic structure of the T domain-DNA complex of the Brachyury transcription factor. Nature389,884-888. (10.1038/39929)
  44. Nemer, G. and Nemer, M. (2001). Regulation of heart development and function through combinatorial interactions of transcription factors. Ann. Med.33,604-610. (10.3109/07853890109002106)
  45. Niwa, H., Yamamura, K. and Miyazaki, J. (1991). Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene108,193-199.
  46. Ogura, T. (2002). In vivoelectroporation: a new frontier for gene delivery and embryology. Differentiation70,163-171. (10.1046/j.1432-0436.2002.700406.x)
  47. Ogura, T. and Evans, R. M. (1995). A retionic acid-triggered cascade of HOXB1 gene activation. Proc. Natl. Acad. Sci. USA92,387-391. (10.1073/pnas.92.2.387)
  48. Redkar, A., Montgomery, M. and Litvin, J.(2001). Fate map of early avian cardiac progenitor cells. Development128,2269-2279. (10.1242/dev.128.12.2269)
  49. Rodriguez-Esteban, C., Tsukui, T., Yonei, S., Magallon, J.,Tamura, K. and Izpisua Belmonte, J. C. (1999). The T-box genes Tbx4 and Tbx5 regulate limb outgrowth and identity. Nature398,814-818. (10.1038/19769)
  50. Ross, R. S., Navankasattusas, S., Harvey, R. P. and Chien, K. R. (1996). An HF-1a/HF-1b/MEF-2 combinatorial element confers cardiac ventricular specificity and establishes an anterior-posterior gradient of expression. Development122,1799-1809. (10.1242/dev.122.6.1799)
  51. Russ, A. P., Wattler, S., Colledge, W. H., Aparicio, S. A.,Carlton, M. B., Pearce, J. J., Barton, S. C., Surani, M. A., Ryan, K.,Nehls, M. C., Wilson, V. and Evans, M. J. (2000). Eomesodermin is required for mouse trophoblast development and mesoderm formation. Nature404,95-99. (10.1038/35003601)
  52. Saijoh, Y., Adachi, H., Mochida, K., Ohishi, S., Hirao, A. and Hamada, H. (1999). Distinct transcriptional regulatory mechanisms underlie left-right asymmetric expression of lefty-1 and lefty-2. Genes Dev. 13,259-269. (10.1101/gad.13.3.259)
  53. Smith, J. (1999). T-box genes: what they do and how they do it. Trends Genet.15,154-158. (10.1016/S0168-9525(99)01693-5)
  54. Srivastava, D., Cserjesi, P. and Olson, E. N.(1995). A subclass of bHLH proteins required for cardiogenesis. Science270,1995-1999. (10.1126/science.270.5244.1995)
  55. Srivastava, D., Thomas, T., Lin, Q., Kirby, M. L., Brown, D. and Olson, E. N. (1997). Regulation of cardiac mesodermal and neural crest development by the bHLH transcription factor, dHAND. Nat. Genet.16,154-160. (10.1038/ng0697-154)
  56. Srivastava, D. and Olson, E. N. (2000). A genetic blueprint for cardiac development. Nature407,221-226. (10.1038/35025190)
  57. Szeto, D. P., Griffin, K. J. P. and Kimelman, D.(2002). HrT is required for cardiovascular development in zebrafish. Development129,5093-5101.
  58. Takeuchi, J. K., Koshiba-Takeuchi, K., Matsumoto, K.,Vogel-Hopker, A., Naitoh-Matsuo, M., Ogura, K., Takahashi, N., Yasuda,K. and Ogura, T. (1999). Tbx5 and Tbx4 genes determine the wing/leg identity of limb buds. Nature398,810-814. (10.1038/19762)
  59. Tomanek, R. J., Ratajska, A., Kitten, G. T., Yue, X. and Sandra,A. (1999). Vascular endothelial growth factor expression coincides with coronary vasculogenesis and angiogenesis. Dev. Dyn.215,54-61. (10.1002/(SICI)1097-0177(199905)215:1<54::AID-DVDY6>3.0.CO;2-0)
  60. Yamada, M., Revelli, J. P., Eichele, G., Barron, M. and Schwartz, R. J. (2000). Expression of chick Tbx-2, Tbx-3, and Tbx-5 genes during early heart development: evidence for BMP2 induction of Tbx2. Dev. Biol.228,95-105. (10.1006/dbio.2000.9927)
  61. Wilkinson, D. G., Bhatt, S. and Herrmann, B. G.(1990). Expression pattern of the mouse T gene and its role in mesoderm formation. Nature343,657-659. (10.1038/343657a0)
  62. Wilkinson, D. G. (1993). Whole Mount in situ Hybridization of Vertebrate Embryos. In Situ Hybridization. Oxford: Oxford University Press.
  63. Zeller, R., Bloch, K. D., Williams, B. S., Arceci, R. J. and Seidman, C. E. (1987). Localized expression of the atrial natriuretic factor gene during cardiac embryogenesis. Genes Dev.1,693-698. (10.1101/gad.1.7.693)
Dates
Type When
Created 21 years, 10 months ago (Oct. 28, 2003, 2:44 a.m.)
Deposited 2 years, 4 months ago (April 27, 2023, 4:37 a.m.)
Indexed 5 days, 17 hours ago (Aug. 30, 2025, 12:28 p.m.)
Issued 21 years, 8 months ago (Dec. 15, 2003)
Published 21 years, 8 months ago (Dec. 15, 2003)
Published Print 21 years, 8 months ago (Dec. 15, 2003)
Funders 0

None

@article{Takeuchi_2003, title={Tbx5specifies the left/right ventricles and ventricular septum position during cardiogenesis}, volume={130}, ISSN={0950-1991}, url={http://dx.doi.org/10.1242/dev.00797}, DOI={10.1242/dev.00797}, number={24}, journal={Development}, publisher={The Company of Biologists}, author={Takeuchi, Jun K. and Ohgi, Makoto and Koshiba-Takeuchi, Kazuko and Shiratori, Hidetaka and Sakaki, Ichiro and Ogura, Keiko and Saijoh, Yukio and Ogura, Toshihiko}, year={2003}, month=dec, pages={5953–5964} }