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First published online February 8, 2008
doi: 10.1242/10.1242/dev.016865

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Wnt signaling: an essential regulator of cardiovascular differentiation, morphogenesis and progenitor self-renewal

Cardiovascular Institute, Institute for Regenerative Medicine, Departments of Medicine and Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.

View larger version (39K): [in this window] [in a new window]   Fig. 1. Cardiac development. Mouse heart development at embryonic day (E) (A) 7.75-8.0, (B) E8.0-8.5, (C) E9.5 and (D) E12.5, and at (E) late embryonic/postnatal stages. Anterior is towards the top. (A-C) The myocardium of the heart develops from two populations of cells called the first heart field (FHF) (red) and a more medial region called the second heart field (SHF) (blue) that lie adjacent to each other at the cardiac crescent stage of development (E7.75-8.0, A). Broken line indicates the midline. (B) Lateral regions of the FHF migrate towards the ventral midline to fuse and form the primitive heart tube, while the SHF remains concentrated in the dorsal pharyngeal mesoderm. (C) Later, SHF cells (blue) migrate into the heart from both anterior and posterior regions, as noted by Isl1 immunostaining and fate mapping with Isl1-cre mice (arrows). (D) By E12.5, the four chambers of the heart are well delineated and septation of the outflow tract is observed so that (E) by late postnatal stages, the outflow tract (OFT) is completely septated and both ventricular and atrial septation are complete in preparation for postnatal life. In D, broken line indicates the OFT septum/cardiac neural crest cells. Ao, aorta; LA, left atrium; LV, left ventricle; PT, pulmonary tract; RA, right atrium; RV, right ventricle.

View larger version (24K): [in this window] [in a new window]   Fig. 2. Wnt signaling pathways. (A) Canonical Wnt signaling (red) is mediated by secreted Wnt ligands (green) binding to a co-receptor complex that consists of Fzd and Lrp5/6 receptors. This activates the intracellular effector protein dishevelled (Dvl), which results in the stabilization and nuclear accumulation of β-catenin, leading to the activation of LEF/TCF-dependent transcription. (B) Non-canonical Wnt signaling involves at least two pathways: the Ca2+/protein kinase C (PKC) and RhoA/JNK pathways. In Ca2+/PKC signaling (purple), Wnt binding activates Fzd receptors causing G protein (G, Gβ, G)-dependent Ca2+ release. This activates PKC and calmodulin-dependent protein kinase II (CaMKII). In RhoA/JNK signaling (yellow), Wnt proteins activate Rho signaling, including Rho/Rac, and JNK through Dvl, leading to ATF/CREB activation. Non-canonical Wnt signaling often antagonizes β-catenin-dependent canonical signaling through mechanisms that remain poorly understood. PM, plasma membrane.

View larger version (22K): [in this window] [in a new window]   Fig. 3. Wnt signaling in early cardiac specification and differentiation. (A) Cross-section of the trunk of a post-gastrulation mouse embryo depicting how various Wnt ligands and Wnt antagonists impinge upon early cardiac mesoderm specification. Dorsal is uppermost. Green tube represents the notochord, the green bottom layer represents the early definitive endoderm, blue indicates the neuroectoderm, red indicates precardiac mesoderm and yellow represents splanchnic mesoderm. Wnt1 and Wnt3a are expressed in neuroectoderm, while Wnt11 and others, including Wnt2a and Wnt2b (not shown), are expressed in precardiac mesoderm. Wnt antagonists crescent and Dkk1 are expressed in the underlying definitive endoderm and inhibit canonical Wnt signaling in the precardiac mesoderm. (B) Studies in ES cells (yellow) show that activation of Wnt signaling prior to, or around the same time as, cardiac mesoderm specification results in increased cardiac differentiation of cardiac myocytes (red), whereas later Wnt signaling activation inhibits cardiac differentiation significantly (Naito et al., 2006). (C) A model showing how Wnt signaling is important for cardiac induction but is inhibitory to later cardiac differentiation. This control could be partly due to the effects of Wnt antagonists secreted from the underlying endoderm.

View larger version (30K): [in this window] [in a new window]   Fig. 4. Expression of Wnt ligands during cardiac morphogenesis. (A) Several Wnt ligands are expressed during early cardiac morphogenesis, as depicted at E9.5. This includes Wnt8a, which is expressed throughout the heart (red) (Jaspard et al., 2000; Kwon et al., 2007), Wnt2a and Wnt2b, which are expressed in the inflow tract and atria during development (yellow) (Monkley et al., 1996; Zakin et al., 1998), and Wnt5a and Wnt11, which are expressed in the outflow tract (green) (Schleiffarth et al., 2007; Zhou et al., 2007). (B-D) In situ hybridization shows the expression of Wnt2a (red) in a posterior-to-anterior gradient in an E9.5 mouse heart, with highest expression in the developing inflow tract (IF) and atria (A). V, ventricle.

View larger version (36K): [in this window] [in a new window]   Fig. 5. Wnt signaling regulates expansion of Isl1+ SHF progenitors through regulation of Isl1 and FGF signaling. (A) Multiple reports have demonstrated that Wnt/β-catenin signaling (red) is required upstream of Isl1 and FGF signaling to promote expansion of SHF stem/progenitor cells (green) (Ai et al., 2007; Cohen et al., 2007; Kwon et al., 2007; Qyang et al., 2007b). (B,C) Expression of an activated β-catenin protein in the secondary heart field (SHF) using the SM22-cre transgenic line leads to a dramatic increase in the number of Isl1+ SHF progenitors in the anterior pharyngeal mesoderm (bracket) and the outflow tract of the mouse embryonic heart (arrowheads). (B,C) Reproduced, with permission, from Cohen et al. (Cohen et al., 2007).