Skip to main content Accessibility help

Cross Talk between Cell–Cell and Cell–Matrix Adhesion Signaling Pathways during Heart Organogenesis: Implications for Cardiac Birth Defects

  • Kersti K. Linask (a1), Shyam Manisastry (a1) and Mingda Han (a1)


The anterior–posterior and dorsal–ventral progression of heart organogenesis is well illustrated by the patterning and activity of two members of different families of cell adhesion molecules: the calcium-dependent cadherins, specifically N-cadherin, and the extracellular matrix glycoproteins, fibronectin. N-cadherin by its binding to the intracellular molecule β-catenin and fibronectin by its binding to integrins at focal adhesion sites, are involved in regulation of gene expression by their association with the cytoskeleton and through signal transduction pathways. The ventral precardiac mesoderm cells epithelialize and become stably committed by the activation of these cell–matrix and intracellular signaling transduction pathways. Cross talk between the adhesion signaling pathways initiates the characteristic phenotypic changes associated with cardiomyocyte differentiation: electrical activity and organization of myofibrils. The development of both organ form and function occurs within a short interval thereafter. Mutations in any of the interacting molecules, or environmental insults affecting either of these signaling pathways, can result in embryonic lethality or fetuses born with severe heart defects. As an example, we have defined that exposure of the embryo temporally to lithium during an early sensitive developmental period affects a canonical Wnt pathway leading to β-catenin stabilization. Lithium exposure results in an anterior–posterior progression of severe cardiac defects.


Corresponding author

Corresponding author. E-mail:


Hide All


Akitaya, T. & Bronner-Fraser, M. (1992). Expression of cell adhesion molecules during initiation and cessation of neural crest cell migration. Dev Dyn 194, 1220.
Altshuler, L.L., Cohen, L., Szuba, M.P., Burt, V.K., Gitlin, M., & Mintz, J. (1996). Pharmacologic management of psychiatric illness during pregnancy: Dilemmas and guidelines. Am J Psychiatry 153, 592606.
Bronner-Fraser, M. (1986). Guidance of neural crest migration. Latex beads as probes of surface–substratum interactions. Dev Biol (N Y 1985) 3, 301337.
Bronner-Fraser, M., Artinger, M., Muschler, J., & Horwitz, A.F. (1992). Developmentally regulated expression of alpha 6 integrin in avian embryos. Development 115, 197211.
Bronner-Fraser, M. & Lallier, T. (1988). A monoclonal antibody against a laminin-heparan sulfate proteoglycan complex perturbs cranial neural crest migration in vivo. J Cell Biol 106, 13211329.
Cachaco, A.S., Chuva de Sousa Lopes, S.M., Kuikman, I., Bajanca, F., Abe, K., Baudoin, C., Sonnenberg, A., Mummery, C.L., & Thorsteinsdottir, S. (2003). Knock-in of integrin beta 1D affects primary but not secondary myogenesis in mice. Development 130, 16591671.
Cohen, L.S., Friedman, J.M., Jefferson, J.W., Johnson, E.M., & Weiner, M.L. (1994). A reevaluation of risk of in utero exposure to lithium. JAMA 271, 146150.
DeHaan, R.L. (1964). Cell interactions and oriented movements during development. J Exp Zool 157, 127138.
de la Cruz, M.V., Sanchez Gomez, C., & Cayre, R. (1991). The developmental components of the ventricles: Their significance in congenital cardiac malformations. Cardiol Young 1, 123128.
de la Cruz, M.V. & Sanchez-Gomez, C. (1998). Straight tube heart. Primitive cardiac cavities vs. primitive cardiac segments. In Living Morphogenesis of the Heart, de la Cruz, M.V. & Markwald, R.R. (Eds.), pp. 8598. Boston: Birkhauser.
de la Cruz, M.V., Sanchez-Gomez, C., & Palomina, M.A. (1989). The primitive cardiac regions in the straight tube heart (Stage 9-) and their anatomical expression in the mature heart: An experimental study in the chick embryo. J Anat 165, 121131.
Edelman, G.M., Cunningham, B.A., & Thiery, J.P. (1990). Introduction. In Morphoregulatory Molecules, Edelman, G.M., Cunningham, B.A. & Thiery, J.P. (Eds.), pp. 15. Indianapolis, IN: Neurosciences Institute Publication.
Eisenberg, C.A., Gourdie, R.G., & Eisenberg, L.M. (1997). Wnt-11 is expresed in early avian mesoderm and required for the differentiation of the quail mesoderm cell line QCE-6. Development 124, 525536.
Ernst, C.L. & Goldberg, J.F. (2002). The reproductive safety profile of mood stabilizers, atypical antipsychotics, and broad-spectrum psychotropics. J Clin Psychiatry 63(Suppl. 4), 4255.
Fassler, R., Rohwedel, J., Maltsev, V., Bloch, W., Lentini, S., Guan, K., Gillberg, D., Hescheler, J., Addicks, K., & Wobus, A. (1996). Differentiation and integrity of cardiac muscle cells are impaired in the absence of beta1 integrin. J Cell Sci 109, 29892999.
George, E.L., Baldwin, H.S., & Hynes, R.O. (1997). Fibronectins are essential for heart and blood vessel morphogenesis but are dispensable for initial specification of precursor cells. Blood 90, 30733081.
George, E.L., Georges-Labouesse, E.N., Patel-King, R.S., Rayburn, H., & Hynes, R.O. (1993). Defects in mesoderm, neural tube and vascular development in mouse embryos lacking fibronectin. Development 119, 10791091.
Gradl, D., Kuhl, M., & Wedlich, D. (1999). The Wnt/Wg signal transducer β-catenin controls fibronectin expression. Mol Cell Biol 19, 55765587.
Hamburger, V. & Hamilton, H.L. (1951). A series of normal stages in the development of the chick embryo. J Morphol 88, 4992.
Hedgepeth, C.M., Conrad, L.J., Zhang, J., Huang, H.C., Lee, V.M.Y., & Klein, P.S. (1997). Activation of the Wnt signaling pathway: A molecular mechanism for lithium action. Dev Biol 185, 8291.
Hurlstone, A.F., Haramis, A.P., Wienholds, E., Begthel, H., Korving, J., Van Eeden, F., Cuppen, E., Zivkovic, D., Plasterk, R.H., & Clevers, H. (2003). The Wnt/beta-catenin pathway regulates cardiac valve formation. Nature 425, 633637.
Imanaka-Yoshida, K., Knudsen, K., & Linask, K.K. (1998). Initial myofibrillogenesis in precardiac mesoderm cultures. Cell Motil Cytoskeleton 39, 5262.
Kamino, K. (1991). Optical approaches to ontogeny of electrical activity and related functional organization during early heart development. Physiol Rev 71, 5391.
Klein, P.S. & Melton, D.A. (1996). A molecular mechanism for the effect of lithium on development. Proc Natl Acad Sci USA 93, 84558459.
Koushik, S.V., Wang, J., Rogers, R., Moskophidis, D., Lambert, N.A., Creazzo, R.L., & Conway, S.J. (2001). Targeted inactivation of the sodium-calcium exchanger (Ncx1) results in the lack of a heartbeat and abnormal myofibrillar organization. FASEB J 15, 12091211.
Krotoski, D. & Bronner-Fraser, M. (1990). Distribution of integrins and their ligands in the trunk of Xenopus laevis during neural crest cell migration. J Exp Zool 253, 139150.
Krotoski, D.M., Domingo, C., & Bronner-Fraser, M. (1986). Distribution of a putative cell surface receptor for fibronectin and laminin in the avian embryo. J Cell Biol 103, 10611071.
Lallier, T. & Bronner-Fraser, M. (1993). Inhibition of neural crest cell attachment by integrin antisense oligonucleotides. Science 259, 692695.
Lash, J.W., Linask, K.K., & Yamada, K.M. (1987). Synthetic peptides that mimic the adhesive recognition signal of fibronectin: Differential effects on cell–cell and cell–substratum adhesion in embryonic chick cells. Dev Biol 123, 411420.
Lee, H.Y., Kleber, M., Hari, L., Brault, V., Suter, U., Taketo, M.M., Kemler, R., & Sommer, L. (2004). Instructive role of wnt/{beta}-catenin in sensory fate specification in neural crest stem cells. Science 303, 10201023.
Linask, K. (2003). Regulation of heart morphology: Current molecular and cellular perspectives on the coordinated emergence of cardiac form and function. Birth Defects Research (Part C) 69, 1424.
Linask, K.K. (1992a). N-cadherin localization in early heart development and polar expression of Na, K-ATPase, and integrin during pericardial coelom formation and epithelialization of the differentiating myocardium. Dev Biol 151, 213224.
Linask, K.K. (1992b). Regulatory role of cell adhesion molecules in early heart development. In Formation and Differentiation of Early Embryonic Mesoderm, Bellairs, R., Sanders, E.J. & Lash, J.W. (Eds.), pp. 301313. New York: Plenum Publishing Corporation.
Linask, K.K. & Gui, Y.H. (1995). Inhibitory effects of ouabain on early heart development and cardiomyogenesis in the chick embryo. Dev Dyn 203, 93105.
Linask, K., Gui, Y.H., Rasheed, R., & Kwon, L. (1992). Pattern development during pericardial coelom formation and specification of the cardiomyocyte cell population by N-cadherin and the Drosophila armadillo protein homologue in the early chick embryo. Mol Biol Cell 3(Suppl.), 206A.
Linask, K.K., Han, M.D., Artman, M., & Ludwig, C.A. (2001). Sodium-calcium exchanger (NCX-1) and calcium modulation. NCX protein expression patterns and regulation of early heart development. Dev Dyn 221, 249264.
Linask, K.K., Knudsen, K.A., & Gui, Y.H. (1997). N-cadherin-catenin interaction: Necessary component of cardiac cell compartmentalization during early vertebrate heart development. Dev Biol 185, 148164.
Linask, K.K. & Lash, J.W. (1986). Precardiac cell migration: Fibronectin localization at mesoderm–endoderm interface during directional movement. Dev Biol 114, 87101.
Linask, K.K. & Lash, J.W. (1988a). A role for fibronectin in the migration of avian precardiac cells. I. Dose dependent effects of fibronectin antibody. Dev Biol 129, 315323.
Linask, K.K. & Lash, J.W. (1988b). A role for fibronectin in the migration of avian precardiac cells. II. Rotation of the heart-forming region during different stages and its effects. Dev Biol 129, 324329.
Linask, K.K. & Lash, J.W. (1990). Fibronectin and integrin distribution on migrating precardiac mesoderm cells. Ann NY Acad Sci 588, 417420.
Linask, K.K. & Lash, J.W. (1993). Early heart development: Dynamics of endocardial cell sorting suggests a common origin with cardiomyocytes. Dev Dyn 195, 6269.
Linask, K.K., Ludwig, C., Han, M.D., Liu, X., Radice, G.L., & Knudsen, K.A. (1998). N-cadherin/catenin-mediated morphoregulation of somite formation. Dev Biol 202, 85102.
Lough, J. & Sugi, Y. (2000). Endoderm and heart development. Dev Dyn 217, 327342.
Luo, Y. & Radice, G.L. (2003). Cadherin-mediated adhesion is essential for myofibril continuity across the plasma membrane but not for assembly of the contractile apparatus. J Cell Sci 116, 14711479.
Markwald, R.R., Nakaoka, T., & Mjaatvedt, C.H. (2000). Overview: Formation of the primary heart tube. In Etiology and Morphogenesis of Congenital Heart Disease: Twenty Years of Progress in Genetics and Developmental Biology, Clark, E.B., Nakazawa, M. & Takao, A. (Eds.), pp. 103114B. Armonk, NY: Futura Publishing Co., Inc.
Markwald, R.R., Trusk, T., & Moreno-Rodriguez, R. (1998). Formation and septation of the tubular heart: Integrating the dynamics of morphology with emerging molecular concepts. In Living Morphogenesis of the Heart, de la Cruz, M.V. & Markwald, R.R. (Eds.), pp. 4384. Boston: Birkhauser.
Marlow, F., Topczewski, J., Sepich, D., & Solnica-Krezel, L. (2002). Zebrafish Rho kinase 2 acts downstream of Wnt11 to mediate cell polarity and effective convergence and extension movements. Curr Biol 12, 876884.
Marvin, M.J., Di Rocco, G., Gardiner, A., Bush, S.M., & Lassar, A.B. (2001). Inhibition of Wnt activity induces heart formation from posterior mesoderm. Genes & Dev 15, 316327.
Moncrieff, J. (1997). Lithium: Evidence reconsidered. Br J Psych 171, 113119.
Pandur, P., Lasche, M., Eisenberg, L., & Kuhl, M. (2002). Wnt-11 activation of a non-canonical Wnt signaling pathway is required for cardiogenesis. Nature 418, 636641.
Peifer, M. (1995). Cell adhesion and signal transduction: The Armadillo connection. Trends Cell Biol 5, 224229.
Radice, G.L., Rayburn, H., Matsunami, H., Knudsen, K.A., Takeichi, M., & Hynes, R.O. (1997). Developmental defects in mouse embryos lacking N-cadherin. Dev Biol 181, 6478.
Rodriguez-Boulan, E. & Nelson, W.J. (1989). Morphogenesis of the polarized epithelial cell phenotype. Science 245, 718724.
Schneider, V.A. & Mercola, M. (2001). Wnt antagonism initiates cardiogenesis in Xenopus laevis. Genes & Dev 15, 304315.
Stambolic, V., Ruel, L., & Woodgett, J.R. (1996). Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells. Curr Biol 6, 16641668.
Sugi, Y. & Markwald, R.R. (1996). Formation and early morphogenesis of endocardial endothelial precursor cells and the role of endoderm. Dev Biol 175, 6683.
Suksaweang, S., Lin, C.M., Jiang, T.X., Hughes, M.W., Widelitz, R.B., & Chuong, C.M. (2004). Morphogenesis of chicken liver: Identification of localized growth zones and the role of beta-catenin/Wnt in size regulation. Dev Biol 266, 109122.
Suzuki, H.R., Solursh, M., & Baldwin, H.S. (1995). Relationship between fibronectin expression during gastrulation and heart formation in the rat embryo. Dev Dyn 204, 259277.
Takeichi, M. (1988). The cadherins: Cell–cell adhesion molecules controlling animal morphogenesis. Development 102, 639655.
Trinh, L.A. & Stainier, D.Y. (2003). Epithelial organization and migration of the myocardial precursors require cell–substratum interaction in zebrafish. Mol Biol Cell 14, 140a.
Trinkaus, J. (1984). Cells into Organs. Englewood Cliffs, NJ: Prentice-Hall, Inc.
Wakimoto, K., Kobayashi, K., Kuro-o, M., Yao, A., Iwamoto, K., Yanaka, N., Kita, S., Nishida, A., Azuma, S., Toyoda, Y., Omori, K., Imahie, H., Oka, T., Kudoh, S., Kohmoto, O., Yazaki, Y., Shigekawa, M., Imai, Y., Nabeshima, Y.-I., & Komuro, I. (2000). Targeted disruption of Na+/Ca++ exchanger gene leads to cardiomyocyte apoptosis and defects in heartbeat. J Biol Chem 275, 3699136998.
Wheelock, M.J. & Johnson, K.R. (2003). Cadherin-mediated cellular signaling. Curr Opin Cell Biol 15, 509514.
Yu, X. & Malenka, R.C. (2003). Beta-catenin is critical for dendritic morphogenesis. Nat Neurosci 6, 11691177.


Cross Talk between Cell–Cell and Cell–Matrix Adhesion Signaling Pathways during Heart Organogenesis: Implications for Cardiac Birth Defects

  • Kersti K. Linask (a1), Shyam Manisastry (a1) and Mingda Han (a1)


Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed