Copyright © 2006, European Society of Cardiology
FGF signalling in the cardiac fields
Cardiovascular Development Group, Department of Experimental Biology, University of Jaen, CU Las Lagunillas s/n, 23071 Jaen, Spain
* Tel.: +34 953 212763; fax: +34 953 211875. Email address: dfranco{at}ujaen.es
Received 3 May 2006; accepted 8 May 2006
See article by Marguerie et al. [6] (pages 50–60) in this issue.
The formation of the heart is a highly dynamic and rather complex process that involves distinct cell types at different developmental stages. For many years, the formation of the muscle layer of the developing heart was considered to be a continuous but single event that leads to the formation of a four-chambered heart from a single, cardiac straight tube. At present, we acknowledge that the formation of the heart is a continuous process, but yet the deployment of the myocardial component is genetically controlled by at least two distinct regulatory mechanisms involving thus two distinct promyocardial subpopulations. The infolding of the cardiac crescents (i.e. first cardiac field) leads to the formation of a straight tube, and subsequently new myocardium is added at both poles, arterial and venous, of the heart (i.e. second heart field). Kelly et al. [1] and Waldo et al. [2] have recently provided compelling evidence that the second heart field originates from a medial mesodermal region and contributes to the right ventricle and outflow tract of the heart in mouse and chick, respectively. More recently, Cai et al. [3] have demonstrated that the contribution of this second heart field also provides promyocardial cell precursors to the developing atrial structures (Fig. 1). In line with these observations, retrospective clonal analyses in the early mouse heart support the notion that two distinct cell lineages, the first and second lineages, contribute to the formation of the embryonic heart [4,5].
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Learning from the fact that two distinctly regulated cell populations form the myocardial heart has launched a quest for new signalling molecules during cardiogenesis, with special attention to the second heart field. Kelly et al. [1] reported that Fgf10-expressing cells contribute to the arterial pole of the heart, and Cai et al. [3] reported that islet-1 expression is crucial to support the deployment of both arterial and venous pole structures. In this new scenario, reinterpretation of previously reported cardiac phenotypes, such as those for Mef2c and Nkx2.5 null mutants, has provided evidence that the lack of these transcription factors results in an impairment of the second heart field deployment. Interestingly, new signalling pathways such as Fox2a, Tbx20 and Foxh1 (Fig. 1) are being discovered which are helping to unravel the complexity of these morphogenetic events.
In this issue, Marguerie et al. [6] have further elaborated the role of fibroblast growth factor (FGF) signalling during cardiac development by carefully describing the cardiac phenotype of two mouse mutant models, Fgf10 and Fgfr2-IIIb null mice. The lack of either the Fgf10 ligand or its putative and most represented receptor in the developing heart, Fgfr2-IIIb, results in overt cardiac phenotypes, thus highlighting the role of FGF signalling during cardiogenesis. At the same time, it also opens new questions about the specific role of each FGF signalling component during the complex morphogenetic process of cardiogenesis. Lack of Fgf10 ligand resulted in an abnormal thoracic position of the heart but otherwise no overt second heart field-derived phenotype. In this context, other FGF family members such as Fgf8 and/or Fgf15 could be partially masking the net Fgf10 effect on the second heart field precursor cells [7–9]. On the other hand, lack of Fgfr2-IIIb resulted in late developmental impairment of the outflow tract and right ventricular free wall but otherwise apparently normal early cell deployment from the second heart field cardiac precursor cells. Whereas there is compelling evidence that Fgf10 ligand targets Fgfr2-IIIb for cell signalling, it remains plausible that other receptors or even other spliced variant receptors from the same gene could be rescuing this signalling pathway. In fact, the observation that ligand and receptor mutant display overtly distinct cardiac phenotypes but have nonetheless rather similar phenotypes in other organs, i.e. lungs, further argues that distinct FGF signalling cascades might be involved during cardiogenesis. At present, Fgf8 and Fgf15 null mutants have been described to display cardiac phenotypes and thus their putative genetic interaction/redundancy with Fgf10/Fgfr2-IIIb should be highly informative.
The work of Marguerie et al. [6] supports the notion that Fgf10/Fgfr2-IIIb signalling in the developing heart is surprisingly dispensable at early developmental stages, but nonetheless it is crucial at later embryonic/foetal stages of cardiac morphogenesis, and in particular to cardiac topological positioning as well as to outflow tract septation. This work is thus seminal in reporting a mouse model of impaired cardiac topology, even if it is a benign condition in humans [10]. On the contrary, impaired outflow tract septation is a rather common condition both in humans [10] as well as in genetically modified mouse models [11–13]. Notably, the septation of the arterial pole is a highly complex process that involves many tissue layers. Tissue distribution of FGF ligands and receptors suggests a key role of these signalling molecules during outflow tract septation [2,9]. The study of Marguerie et al. [6] sheds light on the specific role of Fgfr2-IIIb during arterial pole remodelling, since a significant proportion of mouse embryos lacking Fgfr2-IIIb displays outflow tract defects such as double-outlet right ventricle and overriding aorta without any evidence of cardiac neural crest cell impairment. Interestingly, Fgf8 expression is impaired in the pharyngeal ectoderm in Fgfr2-IIIb null mutants, raising the possibility of a genetic interaction of distinct FGF signalling cascades during cardiac outflow tract formation.
In summary, the observations described by Marguerie et al. [6] nicely exemplify the complexity of the regulatory mechanisms that govern the formation of the heart. At the same time, while shedding light on the importance of specific FGF signalling, the study raises new questions about the genetic interactions of apparently similar pathways. In this line of thinking, an obvious question to be answered in the near future will be to dissect apart the crosstalk between Fgf10/Fgfr2-IIIb and Fgf8/Fgf15 signalling pathways.
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