Building Blocks Of The Heart

The heart is often considered to have a segmental origin, although there is little evidence for a true metameric structure. There are, however, several key processes that can be identified which contribute to the basic ground plan of the heart in the early looping stages. The first is the graded functional activity (beat rate) and graded expression of transcription factor genes that likely betray the graded activity of morphogens in early heart progenitors (Harvey 2002a). The second, mentioned above, is the delayed deployment of the secondary heart field cells to the forming heart. These cells contribute the outflow tract and quite possibly right ventricle (Kelly et al. 2001; Mjaatvedt et al. 2001; Waldo et al. 2001). Region-specific expression patterns of endogenous genes and numerous transgenes suggest that many cardiac genes will be regulated differentially in the primary and secondary heart field lineages. This "modularity" in cardiac gene regulation (Firulli and Olson 1997) may reflect the progressive addition of new anatomical modules or lineage specializations to the heart during the course of vertebrate evolution (Harvey 2002a).

Formation of the caudal (sinuatrial) aspect of the heart requires retinoic acid signaling. Inhibition of retinoid synthesis or receptor signaling leads to hearts that are severely hypoplastic in this area (Rosenthal and Xavier-Neto 2000; Niederreither et al. 2001). Furthermore, excess retinoic acid "atrializes" the ventricular region. It is likely that the caudal region of the heart progenitor zone is exposed to retinoids expressed in the node and primitive streak during gastrulation, and that the timing and

Left

Neural ectoderm

Neural ectoderm

Head mesenchyme

Intra-

embryonic coelom

^Primitive foregut endoderm

Cardiac mesoderm

Figure 2. Diagramatic representation of the key stages in mammalian heart development. Figure shows whole embryos (a,c) or hearts (e,g) (top panels) and representative sections (h,dfh; bottom panels). Myocardium is dark-shaded. The dashed line in a and c represents the approximate plane of section in h and d, respectively. The compass in a represents the approximate axes of the embryos shown. (Adapted from Harvey 2002b.)

Dorsal pericardial mesoderm

Primitive left ventricle

Myocardium

Primitive right ventricle

Trabeculae

Inter-atrial septum

AV septum

Trabeculae

Inter-ventricular septum

Inter-ventricular septum

Figure 2. Diagramatic representation of the key stages in mammalian heart development. Figure shows whole embryos (a,c) or hearts (e,g) (top panels) and representative sections (h,dfh; bottom panels). Myocardium is dark-shaded. The dashed line in a and c represents the approximate plane of section in h and d, respectively. The compass in a represents the approximate axes of the embryos shown. (Adapted from Harvey 2002b.)

spatial dynamics of ingression of heart progenitors through the node and streak restrict the initial domain of retinoid influence to the caudal heart progenitors (Rosenthal and Xavier-Neto 2000). This important aspect of heart development likely occurs prior to heart tube formation and the initiation of myogenesis. Retinoids may also play other broader roles in heart development (Kastner et al. 1997).

A further aspect of early heart development relates to the formation of the muscles of the heart chambers, often called working myocardium. There is now evidence that chamber myocardium arises as a specialization of the more primitive muscle type that constitutes the primary heart tube (Harvey 1999; Christoffels et al. 2000). Expression patterns for genes encoding the hormone atrial natriuretic factor (ANF) and the cytoskeletal protein Chisel show that specification of chamber myocardium occurs in discrete zones at the outer curvature of the looping heart tube (Christoffels et al. 2000; Palmer et al.

2001). Whether these zones are specified by intrinsic patterning processes or by form/function relationships, or both, remains to be determined. The notion of zones of specialized working myocardium on the outer curvature of the looping heart tube (ballooning model of heart chamber formation) is generally incompatible with a segmental view of heart patterning and chamber formation (Christoffels et al. 2000). This radically different view of heart patterning is likely to help in interpretation of mutant phenotypes in mice and congenital heart defects in humans (Harvey 1999; Christoffels et al. 2000).

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