Brief reviewsThe Role of Pitx2 during Cardiac Development: Linking Left–Right Signaling and Congenital Heart Diseases☆
Section snippets
The Left–Right Signaling Cascade
The heart is the first organ to display morphologic asymmetry. However, a left–right differential gene expression program starts earlier in development than does any visible cardiac asymmetry Burdine and Schier 2000, Wright 2001, Yost 1999. Regardless of the site and the method of asymmetry initiation (Boorman and Shimeld 2002), the intermediate pathway converges in all species examined on the activation of the TGF-β superfamily member nodal in the left lateral plate mesoderm (LPM) at early
Pitx2c and Cardiac Looping
The distinct expression pattern of Pitx2c in the LPM at early stages of cardiac development suggested that Pitx2c might play a critical role in establishing the direction of cardiac looping. A first set of Pitx2 overexpression experiments in chicken and Xenopus embryos resulted in abnormal cardiac looping Campione et al. 1999, Logan et al. 1998, Piedra et al. 1998, Ryan et al. 1998, Yoshioka et al. 1998. However, expression of Pitx2c in the LPM of distinct laterality mutant models with abnormal
Functional Role of Pitx2 Isoforms during Cardiovascular Development
Pitx2abc null mice displayed normal cardiac looping, but developed severe embryonic malformations such as abnormal body wall closure. Furthermore, severe cardiac malformations such as right AI (RAI), persistent truncus arteriosus (PTA), DORV, ASD, and VSD Gage et al. 1999, Kitamura et al. 1999, Liu et al. 2001, Lu et al. 1999 have been observed. Some of these cardiac defects also are observed in the Pitx2c isoform-specific knockout (DORV, RAI, ASD, and VSD), suggesting a critical role of Pitx2c
Pitx2 Tissue Distribution during Normal Cardiogenesis
In situ hybridization analyses and cell lineage studies have provided detailed information on Pitx2 isoform distribution during cardiogenesis, which has contributed greatly to the understanding of the etiology of cardiac abnormalities found in Pitx2 loss of function mice.
Cardiac development is a complex and dynamic process (Fishman and Chien 1997). The first myocardial expression of Pitx2c is observed at the cardiac crescent stage confined to the left cardiac crescent (Figure 1), both in mouse
Multiple Tissue Targets of Pitx2 during Cardiovascular Development
The development of the heart is a complex process in which distinct cell types are involved. The promyocardial sheets of the cardiac crescents, give raise to the myocardial and endocardial components of the tubular heart (Fishman and Chien 1997). Subsequently the heart loops and chamber myocardium develops at discrete regions of the outer curvature of the heart (Christoffels et al. 2000). With further development, a subset of migrating neural crest cells invades the endocardial cushions of the
Pitx2 Signaling in the Developing Myocardium
The first experiments of gene deletion resulted in the absence of all Pitx2 isoforms (Pitx2abc) during embryogenesis. In Pitx2abc null mice, the heart invariably displayed RAI, abnormal venous return (AVR), and DORV. In a fraction of Pitx2abc null mutants, DILV, ASD, and VSD also were reported (Table 1) Gage et al. 1999, Kitamura et al. 1999, Lin et al. 1999, Lu et al. 1999. More recently, a series of Pitx2 hypomorphic mutants were generated (Liu et al. 2001). Interestingly, the hearts of
Pitx2 and CNC Proliferation
A recent re-examination of the knockout phenotype has revealed that almost all of the Pitx2abc null mice developed PTA (Kioussi et al. 2002), which is considered a hallmark of CNC deficiency (Kirby et al. 1999). Indeed, Pitx2 is expressed in a subpopulation of (Pax3 positive) CNC cells at E10.5 (Kioussi et al. 2002). Pitx2 expression in the CNC seems to depend on the Wnt/Dvl/β-catenin signaling pathway. Null mutants for the distinct components of this signaling pathway (Dvl2 or Wnt-mediated
Pitx2c and Pharyngeal Arch Remodeling
In addition to its prominent function during myocardial development, a role for Pitx2c in the developing pharyngeal arch mesenchyme has been postulated recently (Liu et al. 2002). Pitx2c is expressed asymmetrically in the developing pharyngeal arches (Liu et al. 2002). Null Pitx2c mutants have revealed a wide range of aortic arch anomalies, such as right aortic arch or double aortic arch (Liu et al. 2002). These cardiac phenotypes are rather similar to those observed in selective CNC ablation
Abnormal Laterality and Congenital Heart Disease: The Pitx2 Contribution
Taking into account all the above, we can reasonably argue that Pitx2 plays a critical role during cardiogenesis in a tissue-specific and isoform-specific manner. Overall, Pitx2 appears to be directing left–right identity to the cardiac venous components, whereas it appears to be modeling the morphologic arrangement of distinct myocardial components in the arterial pole. These data suggest that altered left–right signaling underlies the etiology of several common congenital cardiac
Perspectives
We have revised herein evidence that Pitx2 plays a critical role in distinct cell types during cardiogenesis. Several aspects, however, remain elusive. First, it is not clear why Pitx2 overexpression experiments lead to abnormal cardiac looping, whereas lack of Pitx2 does not alter cardiac turning. Along the same line, it has been reported recently that ectopic expression of Pitx2 correlates with ectopic activation of flectin, an extracellular matrix protein asymmetrically expressed during
Acknowledgements
The authors would like to thank Amelia Aránega and Francisco Navarro for their critical reading of the manuscript. D.F. is supported by a grant from the Ministry of Science and Technology of the Spanish Government (grant #BCM2000-0118-C02-01).
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