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The Role of Pitx2 during Cardiac Development: Linking Left–Right Signaling and Congenital Heart Diseases

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Abstract

Pitx2 is a bicoid-related homeodomain transcription factor that plays a critical role in directing cardiac asymmetric morphogenesis. Ectopic Pitx2c expression in the developing myocardium correlates with double outlet right ventricle (DORV) in laterality mutants. Pitx2 loss of function experiments cause severe cardiovascular defects, such as atrial isomerism (AI), double inlet left ventricle, transposition of the great arteries (TGA), persistent truncus arteriosus (PTA), and abnormal aortic arch (AAA) remodeling. Current studies suggest that Pitx2-mediated signaling during cardiogenesis is conducted within three different cell types: the myocardium, the cardiac neural crest (CNC) cells, and the pharyngeal arch mesenchyme. Impaired Pitx2 function in discrete myocardial regions seems to lead to DORV, AI, and possibly TGA. On the other hand, impaired Pitx2 expression in the CNC leads preferentially to PTA. AAA remodeling is likely to occur owing to impaired cross-talk of the CNC cells with the pharyngeal arch mesenchyme. Thus, Pitx2 appears to be directing left–right identity to the cardiac venous components (e.g., the atria), 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 malformations.

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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