Further Development 18.6: Bilateral Origin of the Heart

Intermediate and Lateral Plate Mesoderm: Heart, Blood, and Kidneys

Although the chick is an excellent model for surgical manipulation, mouse and zebrafish embryos have been more tractable genetically. In the zebrafish, heart precursor cells migrate actively from the lateral edges toward the midline. Several mutations affecting endoderm differentiation disrupt this process, indicating that, as in the chick, the endoderm is critical for cardiac precursor specification and migration. The faust gene, which encodes the Gata5 protein, is expressed in the endoderm and is required for the migration of cardiac precursor cells to the midline and also for their division and specification. It appears to be important in the pathway leading to activation of the zebrafish nkx2-5 gene in the cardiac precursor cells (Reiter et al. 1999). Another particularly interesting zebrafish mutation is miles apart. Its phenotype is limited to cardiac precursor migration to the midline and resembles the cardia bifida seen in experimentally manipulated chick embryos (Figure 1B, C). Differentiation is not affected; the fish form two normal heart tubes, but the tubes are not connected properly to the blood vessels, and thus cannot support circulation. The miles apart gene encodes a protein that regulates the interactions of the cardiac cells with fibronectin, and it is expressed in the endoderm on either side of the midline (Kupperman et al. 2000; Matsui et al. 2007).

In mice, cardia bifida can also be produced by mutations of genes that are expressed in the endoderm. One of these genes, Foxp4, encodes a transcription factor expressed in the early foregut cells, along the pathway the cardiogenic precursors travel toward the midline. In these mutants, each heart primordia develops separately, and the embryonic mouse contains two hearts, one on each side of the body (Figure 1D, E; Li et al. 2004).

**Figure 1** Migration of heart primordia. (A) Cardia bifida (two hearts) in a chick embryo, induced by surgically cutting the ventral midline, thereby preventing the two heart primordia from fusing. (B) Wild-type zebrafish and (C) miles apart mutant, stained with probes for the cardiac myosin light chain. There is a lack of migration in the miles apart mutant. (D) Mouse heart stained with antisense RNA probe to ventricular myosin shows fusion of the heart primordia in a wild-type 13.5-day embryo. (E) Cardia bifida in a Foxp4-deficient mouse embryo. Interestingly, each of these hearts has ventricles and atria, and they both loop and form all four chambers with normal left-right asymmetry.

Literature Cited

Kupperman, E., S. An, N. Osborne, S. Waldron and D. Y. Stainier. 2000. A sphingosine-1-phosphate receptor regulates cell migration during vertebrate heart development. Nature 406: 192–195.
PubMed Link

Li, S., D. Zhou, M. M. Lu and E. E. Morrisey. 2004. Advanced cardiac morphogenesis does not require heart tube fusion. Science 305: 1619–1622.
PubMed Link

Matsui, T., A. Raya, C. Callol-Massot, Y. Kawakami, I. Oishi, C. Rodriguez-Esteban and J. C. Izpisúa Belmonte. 2007. miles-apart-Mediated regulation of cell-fibronectin interaction and myocardial migration in zebrafish. Nat. Clin. Pract. Cardiovasc. Med. 1: S77–S82.
PubMed Link

Reiter, J. F., J. Alexander, A. Rodaway, D. Yelon, R. Patient, N. Holder and D. Y. R. Stanier. 1999. Gata5 is required for the development of the heart and endoderm in zebrafish. Genes Dev. 13: 2983–2995.
PubMed Link

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