Heart-Making Details

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Science  12 Feb 1999:
Vol. 283, Issue 5404, pp. 943b-944b
DOI: 10.1126/science.283.5404.943b

A review by Lewis Wolpert*

Heart Development Richard P. Harvey and Nadia Rosenthal, Eds. Academic, San Diego, 1999. 550 pp. $159.95. ISBN 0-12-329860-1.

When I was writing an introductory textbook on developmental biology, I did not discuss the heart because what was known seemed to introduce no new principles and I could not easily select details that I would want undergraduates to know. The development of the heart is, however, a process of major importance, not least because heart abnormalities are the most common congenital malformations (found in 5 to 8 of every 1000 births). Combining findings from classical embryology and modern molecular techniques, the 65 contributors to Heart Development describe our current knowledge of the processes shaping normal and abnormal hearts. Their studies also suggest why cardiovascular development has proved so hard to understand.

The vertebrate heart, the main system covered in the book, is indeed a complex organ. Study of its development is made difficult partly because its preliminary structures are neither obvious nor easily identified and measured, unlike the cartilage elements that are the beginnings of the embryonic limb. There are also no simple distinctions between either the vascular or electrical conduction systems and the contractile structures. Early on, the cellular precursors, in the chick embryo for example, are present in the primitive streak just behind Hensen's node. A little later the cardiogenic mesoderm lies on each side of the primitive streak and will soon fuse along the midline to form a tubular heart. The anterior region of this tube gives rise to the ventricles, while the atria originate in posterior tissue. Thus the early patterning is along the antero-posterior axis. The movements associated with looping then reverse the positions of atria and ventricles, and also instigate septation and the formation of the four heart chambers. These morphogenetic rearrangements of tissue are poorly understood, and even the formation of the initial heart tube receives scant attention in this book.

Several chapters summarize numerous studies on the induction of the heart mesoderm. Because these studies do not rely on the observation of heart formation but rather document the differentiation of heart muscle cells, they could be quite misleading. It seems that these cells follow a fairly common pathway for differentiation in embryonic stem cell cultures. Other cells important in heart formation include precursors to the endocardium and the conduction system, cells of the vascular system such as endothelial and smooth muscle cells, and cells that form the valves, though these latter structures are barely touched upon. Neural crest cells, primarily responsible for forming the neural tube, also contribute to the formation of the cardiac outflow tracts and great arteries.

The volume emphasizes results from the mouse, frog, chick, and zebrafish, which have become model organisms for studies of heart development. The zebrafish provides an interesting set of mutations affecting the heart, particularly the looping of the tube. Although some of these mutations eliminate the ventricle, none that have been found eliminate the heart completely. This pattern fits with a widely held view that each cardiac chamber and its vascular connections have their own independent control systems.

There are also valuable contributions from Drosophila. Although a much simpler structure than vertebrate hearts, the fruit fly's heart also develops from a tube formed by the fusion of two bilateral primordia. And it is striking that the gene tinman, which is required for heart formation in Drosophila, is related to the Nkx2 genes, which play a key role in vertebrate heart formation. Vertebrate genes of the Nkx2 family can rescue some Drosophila abnormalities associated with mutations in tinman. Surprisingly, there is no evidence that the patterning of the heart tube in vertebrates along the antero-posterior axis is linked to homeobox (Hox) gene expression. Instead, members of the Nkx2 family may provide the positional code, though what specifies the pattern of these genes is not known.

Other questions addressed by the contributors concern the cell lineages that give rise to the heart and the patterns of gene expression, which tell one rather little about mechanisms but are essential molecular descriptions. For example, members of myocyte enhancer family-2 (MEF-2) play several roles in heart development and are important in the activation of many cardiac and skeletal muscle genes. And one of the chamber-specific isoforms of the myosin light chain-2 (MLC-2) protein is the earliest specific marker of the ventricles. In the mouse, knocking out this gene results in failure of the embryo to develop beyond day 12.5. But these are genes involved in the differentiation of only one cell type.

One of the most intriguing aspects of cardiac development is the breaking of bilateral symmetry by the looping of the heart tube to the right of the embryo. Recent studies have dramatically revealed the earliest molecular events in the cell-to-cell signaling that determines this asymmetry and that this signaling occurs in noncardiac mesoderm. The pertinent genes include activin and sonic hedgehog, which also control patterns in many other systems. Perturbation of development, for example, by insertion of beads containing activin can lead to the randomization of heart asymmetry. With the cloning of several of the genes that can randomize asymmetry and the discovery that the inversus viscerum gene codes for axonemal dynein, researchers are getting close to determining how this bilateral asymmetry is established.

The 28 chapters in Heart Development are very well written. The book is beautifully produced and contains many excellent diagrams, but suffers from repetitions of both text and figures (one figure appears twice within 12 pages). It might have been better with fewer chapters and tighter summaries. The volume is indispensable for those who work on the heart, but it may be an expensive luxury for others. Hopefully, with additional progress in our understanding it will be soon out of date.

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