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WIREs Syst Biol Med
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Signaling pathways in early cardiac development

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Abstract Cardiomyocyte differentiation is a complex multistep process requiring the proper temporal and spatial integration of multiple signaling pathways. Previous embryological and genetic studies have identified a number of signaling pathways that are critical to mediate the initial formation of the mesoderm and its allocation to the cardiomyocyte lineage. It has become clear that some of these signaling networks work autonomously, in differentiating myocardial cells whereas others work non‐autonomously, in neighboring tissues, to regulate cardiac differentiation indirectly. Here, we provide an overview of three signaling networks that mediate cardiomyocyte specification and review recent insights into their specific roles in heart development. In addition, we demonstrate how systems level, ‘omic approaches’ and other high‐throughput techniques such as small molecules screens are beginning to impact our understanding of cardiomyocyte specification and, to identify novel signaling pathways involved in this process. In particular, it now seems clear that at least one chemokine receptor CXCR4 is an important marker for cardiomyocyte progenitors and may play a functional role in their differentiation. Finally, we discuss some gaps in our current understanding of early lineage selection that could be addressed by various types of omic analysis. WIREs Syst Biol Med 2011 3 191–205 DOI: 10.1002/wsbm.112 This article is categorized under: Developmental Biology > Developmental Processes in Health and Disease

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A graphical representation of the paired heart primordial in: (a) mouse, (b) amphibian, and (c) avian embryos. Mesodermal tissues are shown in orange (general) and red (cardiac), endoderm in green and epiblast/ectoderm in blue. The heart‐inducing endoderm (darker green) is indicated in each model system; anterior visceral endoderm (AVE) of the mouse, the Dorso‐anterior endoderm (DAE) of the frog and the hypoblast of the chick. In the mouse the endoderm is revealed by ‘peel away’ of the AVE, in the chick and frog the heart forming region (hfr), which is internal to the visible layers is shown in X‐ray view. AVE, anterior visceral endoderm; de, definitive endoderm; hfr, heart forming region; PS, primitive streak; DAE, dorso‐anterior endoderm.

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Description of the symbols used in Figures 2 and 3.

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Wire diagram of SMAD‐dependent and SMAD‐independent signaling pathways activated by members of the TGFβ superfamily of secreted growth factors. TGFβ family members of secreted factors signal through receptor serine/threonine kinases (RS/TKs) or Activin receptors to establish and maintain the expression of early markers for the mesoderm and endoderm. TGFβ I and II, Nodal and Activin use SMAD‐2/3 as second messengers whereas BMPs use SMADs‐1, ‐5, and ‐8. In addition both BMPs and TGFβs (and perhaps other family members) can also signal through the TAB1/TAK, SMAD‐independent signaling pathway.

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Wire diagram of the canonical Wnt/β‐Catenin signaling and non‐canonical Wnt signaling pathways with known function in heart development. In canonical Wnt/β‐Catenin (β‐Cat), activation of the pathway by binding of Wnt ligand to the Frz/LRP5/6 co‐receptor activates signaling through disheveled (dsh) that disrupts the activity of the β‐Cat destruction complex (consisting of adenomatous polyposis coli (APC), Axin and glycogen, synthase kinase 3 (gsk3β), and CK1). Disruption of this complex allows for the nuclear localization of β‐Cat and establishes transcriptional activation of downstream targets by the TCF/β‐Cat complex. Non‐canonical Wnt signaling is established by binding of Wnt11 (or other non‐canonical Wnt) to the Frz receptor (most likely with a different co‐receptor) and this activates downstream phosphorylation of G‐proteins and Jnk. This pathway also regulates intracellular calcium (Ca2+) levels within the cell. The Wnt antagonist Dkk1 acts by disrupting the interaction between Frz and LRP5/6 such that the pathway can no longer be activated even in the presence of Wnt ligand.

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