Building the right ventricle.

Abnormal development of the arterial pole of the heart underlies a significant fraction of congenital heart defects. Critical steps in arterial pole development are formation of the myocardial outflow tract (or conotruncal region) and its subsequent division into separate left and right ventricular outlets. Division of the cylindrical outflow tract is a complex morphogenetic process driven by cardiac neural crest cell influx and associated with rotation of the myocardial wall and cell death, ensuring alignment of the ascending aorta and pulmonary trunk with the left and right ventricles.1–3 The transient nature of the embryonic outflow tract raises existential but also clinically relevant questions as to the origin of this structure and its fate. In an article in this issue, Rana et al have addressed the latter in the developing chick heart with important inferences for the origin of the right ventricle.4 Using scanning confocal microscopy, Rana et al monitored the rise and fall of the myocardial outflow tract. After a 4-fold increase in length to reach a maximum extension the myocardial outflow tract shortens 5-fold. At the same time a nonmyocardial component appears, giving rise to the ascending aorta and pulmonary trunk. Rana et al focused on the retraction phase by following the fate of clusters of DiI labeled cells in ovo at 2 developmental timepoints and concluded that the proximal outflow tract gives rise to a large part of the right ventricular free wall. Although the concept of ventricularisation of the proximal outflow tract (or conal absorption) to form the right ventricular outlet is not new,5–7 the extent to which myocardium initially in the outflow tract contributes to the trabeculated part of the free ventricular wall was unexpected. Concomitant processes, essential for outflow tract division, including broadening of the outflow tract, cell death and outflow tract rotation, were also monitored by Rana et al but are proposed to play less of a role in outflow tract shortening than incorporation into the right ventricular wall. These observations led Rana et al directly from issues of outflow tract fate to the question of how the right ventricle is built. Classical experiments performed in mouse embryos by Viragh and Challice and in chick embryos by Maria Victoria De la Cruz and colleagues demonstrated that the rapidly elongating heart tube grows by recruitment of cells at the poles.6,8 Recent vital dye labeling and molecular analyses have revealed that myocardium at the poles accrues from a population of progenitor cells in pharyngeal mesoderm termed the second heart field which also give rise to smooth muscle at the base of the great arteries.9,10 Second heart field cells originate medially to cells of the cardiac crescent, or first heart field, from which the linear heart tube arises. The first and second heart fields thus correspond to different regions of a cellular continuum and a defining feature of the second heart field is differentiation delay. A number of genetic markers of the second heart field have been identified: the LIM homeodomain transcription factor Isl1 is required for heart tube extension and the fibroblast growth factor encoding genes Fgf10 and Fgf8 are expressed in cells of the second heart field contributing to the arterial pole of the heart; autocrine Fgf8 signaling is required for formation of the right ventricle and outflow tract.11–14 The component of the second heart field contributing to the arterial pole of the heart has been termed the anterior heart field and that subset giving rise to the distal outflow tract and contiguous arterial smooth muscle the secondary heart field.9,10 The right ventricle of the mouse heart is a second heart field derivative. This was initially suggested by the expression profile of an Fgf10 enhancer trap transgene in the second heart field, outflow tract and right ventricle.12 Subsequently, DiI labeling experiments in cultured mouse embryos showed that the linear heart tube gives rise to the left ventricle and that the right ventricle and outflow tract are progressively added to the arterial pole as the heart tube elongates and loops; analysis of the regional myocardial fate of second heart field explants supports this result.15 Lineage analyses using a retrospective marker to study the distribution of clonally related cardiomyocytes and Cre lineage tracing experiments using regulatory elements of second heart field genes Isl1, Tbx1, and Mef2c have further confirmed a second heart field origin of the right ventricle.11,16 –18 Indeed the Mef2c experiments suggest that the entire ventricular septum is a second heart field derivative, at least as defined by expression of the regulatory element used.18 The left and right facing walls of the ventricular septum, however, share the gene expression profiles of the respective free ventricular walls.18,19 Mouse genetics has identified a cascade of transcription factors required for expansion and differentiation of right ventricular precursor cells. Isl1, together with Gata factors, Foxh1 and Nkx2.5, drives Mef2c expression in the second The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Inserm Avenir Group, CNRS UMR6216, Developmental Biology Institute of Marseilles-Luminy, Campus de Luminy, Marseille, France. Correspondence to Robert G. Kelly, CNRS UMR6216, Developmental Biology Institute of Marseilles-Luminy, Campus de Luminy Case 907, 13288 Marseille Cedex 9, France. E-mail [email protected] (Circ Res. 2007;100:943-945.) © 2007 American Heart Association, Inc.