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N-Cadherin: Structure, Function and Importance in the Formation of New Intercalated Disc-Like Cell Contacts in Cardiomyocytes

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Abstract

N-cadherin belongs to a superfamily of calcium-dependent transmembrane adhesion proteins. It mediates adhesion in the intercalated discs at the termini of cardiomyocytes thereby serving as anchor for myofibrils at cell-cell contacts. A large body of data on the molecular structure and function of N-cadherin exists, however, little is known concerning spatial and temporal interactions between the different junctional structures during formation of the intercalated disc and its maturation in postnatal development. The progression of compensated left ventricular hypertrophy to congestive left heart failure is accompanied by intercalated disc remodeling and has been demonstrated in animal models and in patients. The long-term culture of adult rat cardiomyocytes allows to investigate the development of de novo intercalated disc-like structures. In order to analyze the dynamics of the cytoskeletal redifferentiation in living cells, we used the expression of chimeric proteins tagged with the green fluorescent protein reporter. This technique is becoming a routine method in basic research and complements video time-lapse and confocal microscopy. Cultured cardiomyocytes have been used for a variety of studies in cell biology and pharmacology. Their ability to form an electrically coupled beating tissue-like network in culture possibly allows reimplantation of such cells into injured myocardium, where they eventually will form new contacts with the healthy muscle tissue. Several groups have already shown that cardiomyocytes can be grafted successfully into sites of myocardial infarcts or cryoinjuries. Autologous adult cardiomyocyte implantation, might indeed contribute to cardiac repair after infarction, thanks to advances in tissue engineering.

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References

  1. Eppenberger-Eberhardt M, Hauser I, Baechi T, Schaub MC, Brunner UT, Dechesne CA, Eppenberger HM. Immunocytochemical analysis of the regeneration of myofibrils in long-term cultures of adult cardiomyocytes of the rat. Dev Biol 1988;130:1-15.

    Google Scholar 

  2. Gosteli-Peter MA, Harder BA, Eppenberger HM, Zapf J, Schaub MC. Triiodothyronine induces over-expression of alpha-smooth muscle actin, restricts myofibrillar expansion and is permissive for the action of basic fibroblast growth factor and insulin-like growth factor I in adult rat cardiomyocytes. J Clin Invest 1996;98:1737-1744.

    Google Scholar 

  3. Eppenberger-Eberhardt M, Messerli M, Eppenberger HM, Reinecke M. New occurrence of atrial natriuretic factor and storage in secretorially active granules in adult rat ventricular cardiomyocytes in long-term culture. J Mol Cell Cardiol 1993;25:753-757.

    Google Scholar 

  4. Takeichi M. The cadherins: Cell-cell adhesion molecules controlling animal morphogenesis. Development 1988 Apr; 1988;102:639-655.

    Google Scholar 

  5. Takeichi M. Morphogenetic roles of classic cadherins. Curr Opin Cell Biol 1995;7:619-627.

    Google Scholar 

  6. Nose A, Tsuji K, Takeichi M. Localization of specificity determining sites in cadherin cell adhesion molecules. Cell 1990;61:147-156.

    Google Scholar 

  7. Ozawa M, Ringwald M, Kemler R. Uvomorulin-catenin complex formation is regulated by a specific domain in the cytoplasmic region of the cell adhesion molecule. Proc Natl Acad Sci USA 1990;87:4246-4250.

    Google Scholar 

  8. Shapiro L, Fannon AM, Kwong PD, Thompson A, Lehmann MS, Grubel G, Legrand JF, Als Nielsen J, Colman DR, Hendrickson WA. Structural basis of cell-cell adhesion by cadherins. Nature 1995;374:327-337.

    Google Scholar 

  9. Nagar B, Overduin M, Ikura M, Rini JM. Structural basis of calcium-induced E-cadherin rigidification and dimerization. Nature 1996;380:360-364.

    Google Scholar 

  10. Leahy DJ. Implications of atomic-resolution structures for cell adhesion. Annu Rev Cell Dev Biol 1997;13:363-393.

    Google Scholar 

  11. Matsunami H, Miyatani S, Inoue T, Copeland NG, Gilbert DJ, Jenkins NA, Takeichi M. Cell binding specificity of mouse R-cadherin and chromosomal mapping of the gene. J Cell Sci 1993;106:401-409.

    Google Scholar 

  12. Inuzuka H, Redies C, Takeichi M. Differential expression of R-and N-cadherin in neural and mesodermal tissues during early chicken development. Development 1991;113:959-967.

    Google Scholar 

  13. Brieher WM, Yap AS, Gumbiner BM. Lateral dimerization is required for the homophilic binding activity of C-cadherin. J Cell Biol 1996;135:487-496.

    Google Scholar 

  14. Nagafuchi A, Takeichi M. Cell binding function of E-cadherin is regulated by the cytoplasmic domain. Embo J 1988;7:3679-3684.

    Google Scholar 

  15. Volk T, Geiger B. A 135-kd membrane protein of intercellular adherens junctions. Embo J 1984;3:2249-2260.

    Google Scholar 

  16. Volk T, Geiger B. A-CAM: A 135-kD receptor of intercellular adherens junctions. I. Immunoelectron microscopic localization and biochemical studies. J Cell Biol 1986;103:1441-1450.

    Google Scholar 

  17. Soler AP, Knudsen KA. N-cadherin involvement in cardiac myocyte interaction and myofibrillogenesis. Dev Biol 1994;162:9-17.

    Google Scholar 

  18. Imanaka-Yoshida K, Knudsen KA, Linask KK. N-cadherin is required for the differentiation and initial myofibrillogenesis of chick cardiomyocytes. Cell Mot Cytoskeleton 1998;39:52-62.

    Google Scholar 

  19. Linask KK, Knudsen KA, Gui YH. N-cadherin-catenin interaction: Necessary component of cardiac cell compartmentalization during early vertebrate heart development. Dev Biol 1997;185:148-164.

    Google Scholar 

  20. Hertig CM, Butz S, Koch S, Eppenberger-Eberhardt M, Kemler R, Eppenberger HM. N-cadherin in adult rat cardiomyocytes in culture. II. Spatio-temporal appearance of proteins involved in cell-cell contact and communication. Formation of two distinct N-cadherin/catenin complexes. J Cell Sci 1996;109:11-20.

    Google Scholar 

  21. Hertig CM, Eppenberger Eberhardt M, Koch S, Eppenberger HM. N-cadherin in adult rat cardiomyocytes in culture. I. Functional role of N-cadherin and impairment of cell-cell contact by a truncated N-cadherin mutant. J Cell Sci 1996;109:1-10.

    Google Scholar 

  22. Ong LL, Kim N, Mima T, Cohen-Gould L, Mikawa T. Trabecular myocytes of the embryonic heart require N-cadherin for migratory unit identity. Dev Biol 1998;193:1-9.

    Google Scholar 

  23. Radice GL, Rayburn H, Matsunami H, Knudsen KA, Takeichi M, Hynes RO. Developmental defects in mouse embryos lacking N-cadherin. Dev Biol 1997;181:64-78.

    Google Scholar 

  24. Fujio Y, Yamadahonda F, Sato N, Funai H, Wada A, Awata N, Shibata N. Disruption of cell-cell adhesion in an inbred strain of hereditary cardiomyopathic hamster (bio 14.6). Cardiovasc Res 1995;30:899-904.

    Google Scholar 

  25. Wang X, Gerdes AM. Chronic pressure overload cardiac hypertrophy and failure in guinea pigs: III. Intercalated disc remodeling. J Mol Cell Cardiol 1999;31:333-343.

    Google Scholar 

  26. Severs NJ. Pathophysiology of gap junctions in heart disease. J Cardiovasc Electrophysiol 1994;5:462-475.

    Google Scholar 

  27. Kaprielian RR, Gunning M, Dupont E, Sheppard MN, Rothery SM, Underwood R, Pennell DJ, Fox K, Pepper J, Poole-Wilson PA, Severs NJ. Downregulation of immunodetectable connexin-43 and decreased gap junction size in the pathogenesis of chronic hibernation in the human left ventricle. Circulation 1998;97:651-660.

    Google Scholar 

  28. Arber S, Hunter JJ, Ross J, Jr., Hongo M, Sansig G, Borg J, Perriard JC, Chien KR, Caroni P. MLP-deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure. Cell 1997;88:393-403.

    Google Scholar 

  29. Jongen WMF, Fitzgerald DJ, Asamoto M, Piccoli C, Slaga TJ, Gros D, Takeichi M, Yamasaki H. Regulation of connexin 43-mediated gap junctional intercellular communication by calcium in mouse epidermal cells is controlled by E-cadherin. J Cell Biol 1991;114:545-556.

    Google Scholar 

  30. Kostin S, Hein S, Bauer EP, Schaper J. Spatiotemporal development and distribution of intercellular junctions in adult rat cardiomyocytes in culture. Circ Res 1999;85:145-167.

    Google Scholar 

  31. Zuppinger C, Schaub MC, Eppenberger H. Dynamics of early contact formation in cultured adult rat cardiomyocytes studied by N-cadherin fused to green fluorescent protein. J Moll Cell Cardiol 2000;32:539-555.

    Google Scholar 

  32. Butz S, Kemler R. Distinct cadherin-catenin complexes in Ca-2+dependent cell-cell adhesion. FEBS Letters 1994;355:195-200.

    Google Scholar 

  33. Shibamoto S, Hayakawa M, Takeuchi K, Hori T, Miyazawa K, Kitamura N, Johnson KR, Wheelock MJ, Matsuyoshi N, Takeichi M, Ito F. Association of p120, a tyrosine kinase substrate with E-cadherin/catenin complexes. J Cell Biol 1995;128:949-957.

    Google Scholar 

  34. Daniel JM, Reynolds AB. The catenin p120ctn interacts with Kaiso, a novel BTB/POZ domain zinc finger transcription factor. Mol Cell Biol 1999;19:3614-3623.

    Google Scholar 

  35. Cubitt AB, Heim R, Adams SR, Boyd AE, Gross LA, Tsien RY. Understanding, improving and using green fluorescent proteins. Trends Biochem Sci 1995;20:448-455.

    Google Scholar 

  36. Heim R, Cubitt AB, Tsien RY. Improved green fluorescence. Nature 1995;373:663-664.

    Google Scholar 

  37. Ludin B, Matus A. GFP illuminates the cytoskeleton. Trends Cell Biol 1998;8:72-77.

    Google Scholar 

  38. Auerbach D, Rothen Ruthishauser B, Bantle S, Leu M, Ehler E, Helfman D, Perriard JC. Molecular mechanisms of myofibril assembly in heart. Cell Struct Funct 1997;22:139-146.

    Google Scholar 

  39. Helfman DM, Berthier C, Grossman J, Leu M, Ehle E, Perriard E, Perriard JC. Nonmuscle tropomyosin-4 requires coexpression with other low molecular weight isoforms for binding to thin filaments in cardiomyocytes. J Cell Sci 1999;112:371-380.

    Google Scholar 

  40. Eppenberger HM, Zuppinger C. In vitro reestablishment of cell-cell contacts in adult rat cardiomyocytes. Functional role of transmembrane components in the formation of new intercalated disk-like cell contacts. FASEB J 1999;13:S84-S89.

    Google Scholar 

  41. Rust EM, Westfall MV, Metzger JM. Stability of the contractile assembly and Ca2.-activated tension in adenovirus infected adult cardiac myocytes. Mol Cell Biochem 1998;181:143-155.

    Google Scholar 

  42. Daetwyler DA, Eppenberger HM, Koller D, Bailey JE, Magyar JP. Efficient gene delivery into adult cardiomyocytes by recombinant Sindbis virus. J Mol Med 1999;77 (12):859-864.

    Google Scholar 

  43. Parenteau N. Skin: The first tissue-engineered products. Sci Am 1999;280:83-84.

    Google Scholar 

  44. Kajstura J, Leri A, Finato N, Di Loreto C, Beltrami CA, Anversa P. Myocyte proliferation in end-stage cardiac failure in humans. Proc Natl Acad Sci USA 1998;95:8801-8805.

    Google Scholar 

  45. Soonpaa MH, Koh GY, Klug MG, Field LJ. Formation of nascent intercalated disks between grafted fetal cardiomyocytes and host myocardium. Science 1994;264:98-101.

    Google Scholar 

  46. Reinecke H, Zhang M, Bartosek T, Murry CE. Survival, integration, and differentiation of cardiomyocyte grafts: A study in normal and injured rat hearts. Circulation 1999;100:193-202.

    Google Scholar 

  47. Sakai T, Li RK, Weisel RD, Mickle DA, Kim EJ, Tomita S, Jia ZQ, Yau TM. Autologous heart cell transplantation improves cardiac function after myocardial injury. Ann Thorac Surg 1999;68:2074-2080.

    Google Scholar 

  48. Taylor DA, Atkins BZ, Hungspreugs P, Jones TR, Reedy MC, Hutcheson KA, Glower DD, Kraus WE. Regenerating functional myocardium: Improved performance after skeletal myoblast transplantation. Nat Med 1998;4:929-933.

    Google Scholar 

  49. Dorfman J, Duong M, Zibaitis A, Pelletier MP, Shum-Tim D, Li C, Chiu RC. Myocardial tissue engineering with autologous myoblast implantation. J Thorac Cardiovasc Surg 1998;116:744-751.

    Google Scholar 

  50. Polonchuk LO, Elbel J, Eckert-Blum J, Wintermantel E, Eppenberger HM. Titanium dioxide ceramic controls the differentiated phenotype of adult rat ventricular myocytes in vitro. Biomaterials 2000;21:539-550.

    Google Scholar 

  51. Koh GY, Soonpaa MH, Klug MG, Field LJ. Long-term survival of AT-1 cardiomyocyte grafts in syngeneic myocardium. Am J Physiol 1993;264:H1727-1733.

    Google Scholar 

  52. Watanabe E, Smith DM, Delcarpio JB, Sun J, Smart FW, VanMeter CH, Claycomb WC. Cardiomyocyte transplantation in a porcine myocardial infarction model. Cell Transplantation 1998;7(3):239-246.

    Google Scholar 

  53. Klug MG, Soonpaa MH, Koh GY, Field LJ. Genetically selected cardiomyocytes from differentiating embronic stem cells form stable intracardiac grafts. J Clin Invest 1996;98:216-224.

    Google Scholar 

  54. Koh GY, Klug MG, Soonpaa MH, Field LJ. Differentiation and long-term survival of C2C12 myoblast grafts in heart. J Clin Invest 1993;92:1548-1554.

    Google Scholar 

  55. Van Meter CH, Jr., Claycomb WC, Delcarpio JB, Smith DM, deGruiter H, Smart F, Ochsner JL. Myoblast transplantation in the porcine model: A potential technique for myocardial repair. J Thorac Cardiovasc Surg 1995;110:1442-1448.

    Google Scholar 

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Authors and Affiliations

  1. Dept. of Biology, Institute of Cell Biology, Swiss Federal Institute of Technology ETH, CH-8093, Zurich, Switzerland

    C. Zuppinger, M. Eppenberger-Eberhardt & H.M. Eppenberger

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  1. C. Zuppinger
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  2. M. Eppenberger-Eberhardt
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  3. H.M. Eppenberger
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Zuppinger, C., Eppenberger-Eberhardt, M. & Eppenberger, H. N-Cadherin: Structure, Function and Importance in the Formation of New Intercalated Disc-Like Cell Contacts in Cardiomyocytes. Heart Fail Rev 5, 251–257 (2000). https://doi.org/10.1023/A:1009809520194

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