WNT/Frizzled-2 Signaling Induces Aggregation and Adhesion among Cardiac Myocytes by Increased Cadherin–β-Catenin Complex

Abstract

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.

Expression of Dishevelled‐1 in wound healing after acute myocardial infarction: possible involvement in myofibroblast proliferation and migration

“…These results are partially supported by some studies in vitro, in which depletion of cytosolic β-catenin induced apoptosis and suppressed proliferation [24], whereas high levels of cytosolic β-catenin (through constitutive stabilization) resulted in elevated proliferation and reduced apoptosis [5]. Some developmental studies indicate that Wnt /β-catenin pathway have little or no impact on cardiac myocytes and fibroblasts proliferation or differentiation [25]. This controversy is not hard to understand because the wounding healing process after MI is considered as a process involving incomplete heart regeneration, different from heart development.…”

Chick pulmonaryWnt5adirects airway and vascular tubulogenesis

“…Wnt5a moderates many cellular events, including cell adhesion (Jonsson and Andersson, 2001;Torres et al, 1996;Toyofuku et al, 2000;Weeraratna et al, 2002), migration (Jonsson and Andersson, 2001), proliferation (Liang et al, 2003;Yamaguchi et al, 1999) and differentiation (He et al, 1997;Kuhl et al, 2001;Kuhl et al, 2000;Sheldahl et al, 1999). These findings suggest that Wnt5a is a good candidate for coordinating pulmonary air and vascular pattern formation.…”

The Multiple Phases and Faces of Wnt Signaling During Cardiac Differentiation and Development

“…92 Wnt11 has been shown to regulate N-cadherin expression in the quail mesodermal progenitor cell line QCE6, 59 and N-cadherin expression and function in neonatal rat cardiomyocytes is regulated by Wnt/Fz2 signaling. 93 Wnt11 knockout embryos display defects in the OFT (see below) 77 but also thinner ventricular walls and less trabeculae. A detailed analysis indicated defects in N-cadherin/␤-catenin mediated cell adhesion as well.…”

“…32,[61][62][63][64]66 Linear heart tube formation ␤-catenin required for cell-cell contact Supports cell adhesion 59,77,88,89,92,93 ; required for morphogenesis 87,89,95 OFT morphogenesis Required for septation (CNCCs) [103][104][105] Required for cytoskeleton formation and cell-cell interactions 77,[106][107][108][109][110][111] Cardiac looping Required (zebrafish) 98 Not known…”