Wnt6 signaling regulates heart muscle development during organogenesis

Abstract

Mesodermal tissue with heart forming potential (cardiogenic mesoderm) is induced during gastrulation. This cardiogenic mesoderm later differentiates into heart muscle tissue (myocardium) and non-muscular heart tissue. Inhibition of Wnt/β-catenin signaling is known to be required early for induction of cardiogenic mesoderm; however, the identity of the inhibiting Wnt signal itself is still elusive. We have identified Wnt6 in Xenopus as an endogenous Wnt signal, which is expressed in tissues close to and later inside the developing heart. Our loss-of-function experiments show that Wnt6 function is required in the embryo to prevent development of an abnormally large heart muscle. We find, however, that Wnt6 is not required as expected during gastrulation stages, but later during organogenesis stages just before cells of the cardiogenic mesoderm begin to differentiate into heart muscle (myocardium). Our gain-of-function experiments show that Wnt6 and also activated canonical Wnt/β-catenin signaling are capable of restricting heart muscle development at these relatively late stages of development. This repressive role of Wnt signaling is mediated initially via repression of cardiogenic transcription factors, since reinstatement of GATA function can rescue expression of other cardiogenic transcription factors and downstream cardiomyogenic differentiation genes.

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

“…86 A natural in vivo ligand for this repressive effect of Wnt/␤-catenin signaling on cardiogenesis could be Wnt6. 87 Overexpression of Wnt6 in transgenic Xenopus embryos using a heat shock-inducible promotor during stages of terminal differentiation resulted in decreased cardiac structures. In contrast, depleting Wnt6 by use of antisense morpholino oligonucleotides resulted in enlarged cardiac structures.…”

“…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…”

Tmem88a mediates GATA-dependent specification of cardiomyocyte progenitors by restricting WNT signaling

“…Understanding the function of the WNT pathway for CP specification has been more challenging, as canonical WNT signaling both promotes and restrains CP specification (Kwon et al, 2007;Lavery et al, 2008;Naito et al, 2006;Paige et al, 2010;Tzahor, 2007;Ueno et al, 2007). During gastrulation, WNT activity induces ventrolateral mesoderm to establish the precardiac territory.…”

Canonical WNT Signaling Enhances Stem Cell Expression in the Developing Heart Without a Corresponding Inhibition of Cardiogenic Differentiation

“…Studies with ES cells indicated that canonical WNTs could have a positive influence of cardiac tissue formation [23][24][25][26][27][28]. Recent investigations in the whole embryo suggested that timing during development may determine whether cardiac differentiation is stimulated or suppressed by canonical WNTs, and have prompted a modified hypothesis that these molecules have a biphasic influence on heart development [12,13,16,26,30]. Thus, it has been proposed that exposure to canonical WNT signals before gastrulation is required for cardiac induction and/or expansion of cardiac progenitors, whereas once gastrulation begins, suppression of these same signals is necessary to allow cardiac differentiation to continue.…”

“…Yet, WNT regulation of cardiogenesis may not be so clear cut, as investigations with embryonic stem cells have indicated that both canonical and noncanonical WNTs promote cardiac differentiation [23][24][25][26][27][28]. Recent studies suggested that canonical WNT regulation of cardiac differentiation may be phasic, either promoting or inhibiting cardiogenesis, depending on the stage in development [12,13,16,26,29,30].…”