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© The Rockefeller University Press,
0021-9525/2000//225 $5.00
The Journal of Cell Biology, Volume 150, Number 1,
, 2000 225-242
Original Article |
WNT/Frizzled-2 Signaling Induces Aggregation and Adhesion among Cardiac Myocytes by Increased Cadherin–β-Catenin Complex
toyofuku{at}mr-path.med.osaka-u.ac.jp
Wingless is known to be required for induction of cardiac mesoderm in Drosophila, but the function of Wnt family proteins, vertebrate homologues of wingless, in cardiac myocytes remains unknown. When medium conditioned by HEK293 cells overexpressing Wnt-3a or -5a was applied to cultured neonatal cardiac myocytes, Wnt proteins induced myocyte aggregation in the presence of fibroblasts, concomitant with increases in β-catenin and N-cadherin in the myocytes and with E- and M-cadherins in the fibroblasts. The aggregation was inhibited by anti–N-cadherin antibody and induced by constitutively active β-catenin, but was unaffected by dominant negative and dominant positive T cell factor (TCF) mutants. Thus, increased stabilization of complexed cadherin–β-catenin in both cell types appears crucial for the morphological effect of Wnt on cardiac myocytes. Furthermore, myocytes overexpressing a dominant negative frizzled-2, but not a dominant negative frizzled-4, failed to aggregate in response to Wnt, indicating frizzled-2 to be the predominant receptor mediating aggregation. By contrast, analysis of bromodeoxyuridine incorporation and transcription of various cardiogenetic markers showed Wnt to have little or no impact on cell proliferation or differentiation. These findings suggest that a Wnt–frizzled-2 signaling pathway is centrally involved in the morphological arrangement of cardiac myocytes in neonatal heart through stabilization of complexed cadherin– β-catenin.
Key Words: Wnt • frizzled • cardiac myocytes • cadherin • β-catenin
© 2000 The Rockefeller University Press
Abbreviations used in this paper: BrdU, bromodeoxyuridine; CRD, cysteine-rich domain; ECM, extracellular matrix; EGFP, enhanced GFP; GFP, green fluorescent protein; GPI, glycophosphatidylinositol; GSK, glycogen synthase kinase; GST, glutathione-S-transferase; LEF, lymphoid enhancer factor; MHC, myosin heavy chain
/β; RT, reverse transcriptase; TCF, T cell factor.
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