Cardiac lineage selection: integrating biological complexity into computational models

A graphical representation of the movement of heart precursors in an amphibian embryo from the beginning of gastrulation to the early tailbud at which point heart cells have migrated to their final destination in the embryo. The red spot marks the approximate location of heart precursors at that stage and the arrow represents the direction of their migration. (Redrawn after Copenhaver in Refs3, 4).

Schematic overview of cardiac lineage selection. All cells in the embryo start out as undifferentiated epiblast. Through the process of gastrulation, the three germ layers, ectoderm, mesoderm, and endoderm, form. Mesoderm and endoderm initially exit from the streak as a mixed mesendodermal population marked by expression of the transcription factor T/brachyury but quickly sorts out into morphologically and molecularly distinct mesoderm and endoderm. Mesodermal cells then take on specific regional identities under the influence of environmental cues. At this stage, cells destined to form the primary heart tube express the transcription factors Nkx2.5 and Tbx5. Finally, these cells go on to form beating cardiomyocytes that express myosin heavy chain α and other contractile proteins.

Wire diagram of the major molecular interactions that are key to the establishment and early functioning of the dorsal organizing centers. Essentially, canonical Wnt/β‐Catenin (β‐Cat) signaling through disheveled (dsh) disrupts the β‐Catenin destruction complex [consisting of adenomatous polyposis coli (APC), Axin and glycogen, synthase kinase 3 (gsk3β)], which allows for the nuclear localization of β‐Catenin and establishes the expression of dorsal molecular markers such as twins, siamois, and goosecoid and establishes a domain of nodal signaling. Nodal and other members of the transforming growth factor β (TGFβ) family of secreted factors, signaling through receptor serine/threonine kinases (RS/Tks) or activin receptors (ActIIR, ALK4) establish markers for the dorsal mesoderm and endoderm including brachyury (bra) and other markers for the dorsal mesoderm and endoderm such as cerberus, lim‐1 (lim), and dikkopf‐1 (dkk1). Explanation of symbols used can be found in Table 1.

Wire diagram of the major signaling networks that induce the expression of early mesendodermal markers. At this stage, the FGF signaling pathway interacts closely with members of the TGFβ family of secreted factors signaling through receptor serine/threonine kinases (RS/Tks) or activin receptors (ActIIR, ALK4) to establish and maintain the expression of early markers for the mesoderm and endoderm and also establishes chordin (chd), dhand, ehand, and sonic hedgehog (shh) as well as endodermal markers such as sox17 and foxA2 (other abbreviations are the same as in Figure 3). Explanation of symbols used can be found in Table 1.

Waddington's Epigenetic Landscape. While clearly no longer an accurate representation of the emerging field of epigenetics, still a useful visual tool to describe the phenomenon by which developmental fates become progressively limited. The downward slope represents developmental time. As the ball (cell) rolls down the slope (differentiates), its path will follow one of a few possible paths. At each node, the developmental potential of the cell becomes progressively more limited until it reaches a point at which it has only one possible fate.58 In the context of this review, each fork in the developmental path likely represents a local change in the transcriptional state of the differentiating cell.

A partial, non‐comprehensive wire diagram summarizing some of the factors known to play key roles in cardiomyocyte lineage selection and their relative positions within the cell. The main signaling feature at this phase of development is mediated by antagonists of the canonical Wnt/β‐Catenin signaling pathway. Normally, signaling through the β‐Catenin pathway inhibits the expression of genes such as Hex, Naked (nkd) and nemo‐like kinase (nlk); however, inhibition of this pathway by Wnt11 and Dkk‐1 allows for the transcription of these factors. In addition, nodal signaling patterns both endodermal (cerberus, mix, FoxH1) and mesodermal (Nkx2.5 and Tbx5). For the sake of simplicity, both of these are shown on the same diagram. In addition, other signaling pathways that are thought to play roles in the maintenance and proliferation of cardiac phenotypes at these stages (BMP and FGF) are not shown in this diagram (other abbreviations same as in Figures 3 and 4).