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Expression and Function of Pitx2 in Chick Heart Looping

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Rightward looping of the straight heart tube, a vital process for the formation of multichambered heart, is the first morphological manifestation of left-right (L-R) asymme try during vertebrate embryonic development. In the developing chick embryo, sophisticated genetic pathways involving numerous signaling molecules and transcription factors in the regulation of dextral cardiac looping have been recently established. Among these asymmetric molecules is Pitx2, a paired-like transcription factor expressed in the left side lateral plate mesoderm and left half of the cardiac tube. Studies demonstrated that Pitx2 resides downstream of the Shh/Nodal signaling pathway and functions to execute the L-R developmental program.

Chick Cardiac Looping

The heart is the first functional organ to form in vertebrate embryos. It arises through a complex series of morphogenetic interactions involving cells from several embryonic origins.1 In the chick, cardiac precursor cells are originally located in the epiblast lateral to the primitive streak, and move through the primitive groove to join the mesoderm during gastrulation.2 These cardiac precursors continue to migrate in an anterior/lateral direction, forming a pair of cardiac primordia residing in the lateral mesoderm on either side of the primitive streak. Beginning at HH-stage 6,3 with the formation of head fold and anterior intestinal portal, the lateral regions of anterior embryo begin to approach each other to form the foregut. As part of this process, the two cardiac primordia, now each forms a heart tube, are brought together on the ventral surface of the forming foregut. From HH-stage 9, these two separate cardiac tubes meet at the ventral midline and fuse to form a single straight heart tube. It contains three layers: a thin outer layer of myocardium, a middle layer of extracellular matrix known as cardiac jelly, and an inner layer of endocardium. The cardiac tube then undergoes a dextral looping, a feature which is conserved among all vertebrate species.

The dextral heart looping that breaks the bilateral symmetry of the embryo is vital to normal cardiac morphogenesis and laterality. Failure to establish the proper left-right (L-R) asymmetric development leads to misplacement of internal organs that is classified as isomerism (symmetrical organ situs), heterotaxia (one or more organs develop with reversed L-R polarity), and situs inversus (complete reversion of the L-R axis). Cardiac looping is a complex process rather than a simple rightward bending of the straight heart tube (for a review see ref. 4). In the developing chick embryo, heart looping starts around HH-stage 10, and becomes discernible at HH-stage 11. During this period, the straight heart tube is transformed into a c-shaped loop through the rightward flapping/lateralization of the primitive ventricular bend and the right kinking of the primitive conus.4,5 This process is followed by the transformation of the c-shaped cardiac loop into the s-shaped loop via significant morphogenetic events. The later contains four morphologically distinguishable components: the sinus venosus, the primitive atria, the primitive ventricular bend, and the primitive conus, establishing architecture for the formation of the multichambered heart (for a review see ref. 4).

The mechanisms of heart looping have been studied extensively in the chick. Heart looping appears to be intrinsic to the heart with consistent rightward looping directionality.6,7 Patten,8 put forward a model in which the dextral-looping was thought to be driven by compressive axial forces as the heart grows longer within a confined space. However, he could not explain the preference for rightward looping. Several hypotheses were proposed that postulated the involvement of differential cell movement, cell redistribution, or differential rate of cell proliferation and cell death in myocardial walls across the heart tube (for a review see ref. 4).6,9 Others"took account of cardiac jelly pressure or an initial tension in the dorsal mesocardium.10,11 But none of them was experimentally proven or consistent with all available experimental evidence.

Molecular Cascades Regulating Cardiac Looping

Although the cellular mechanisms that drive cardiac looping remain unclear, significant progress has been made in the past few years regarding the molecular basis for the rightward looping of the heart tube.12 Classic transplantation experiments suggested that directionality of heart looping is determined during gastrulation and controlled by the lateral plate mesoderm (LPM).13 It is now known that dextral heart looping is controlled by a set of genes that interact to establish the L-R asymmetric developmental program. The molecules involved in breaking the L-R symmetry and regulating heart looping directionality are mostly derived from the original studies in the chick. The seminal work of Levin et al14 initiated a wave of molecular studies on L-R patterning. In the chick, the L-R asymmetric gene expression is first seen in Hensen's node and perinodal area. During early gastrulation, asymmetric expression of Activin- βB and gene encoding for its type II receptor (cAct-RIIa) in the right side of Hensen's node inhibits otherwise symmetrically expressed Sonic hedgehog (Shh) in the right side of the node, which leads to the restriction of Shh expression to the left side around HH-stage 5.14,15 The left-sided Shh expression in Hensen's node is maintained by BMP4 that, together with FGF4 and FGF8, exhibits asymmetric expression in the right side of Hensen's node and repress expression of Shh and the Shh-dependent pathway.16-18 The asymmetric expression of these genes in the node is unique to the chick and not found in other species including mice and Xenopus at similar developmental stages. Other genes that exhibit an asymmetric expression pattern in and around Hensen's node and participate in the development of the L-R axis in chick embryos include Wnt-8c, PKI, and N-cadherin.19-21

The L-R asymmetric pathway established in Hensen's node is then converted into much broader domains of side-specific gene expression in the LPM. On the left side of the chick embryo, the asymmetric Shh expression is responsible for the asymmetric expression of the Nodal gene that encodes a member of TGF-β superfamily to the left LPM around HH-stage 6.14,15,22 This induction of Nodal by Shh is mediated by the product of the Cerberus-related gene Caronte (Car) that antagonizes the repressive activity of bilaterally expressed BMPs.23-25 The chick CFC, a member of the EGF-CFC family, appears to maintain the asymmetric Nodal expression in the LPM that is crucial for establishing the L-R asymmetric program.26 Alteration of Nodal expression in the LPM randomizes the directionality of heart looping.15 Genes downstream from the Nodal signaling in the left LPM include the paired-type homeobox gene Pitx2, the homeobox gene Nkx3.2, and the zinc finger gene SnR. Nodal functions as an activator for both Pitx2 and Nkx3.2 but a repressor for SnR.23,27-29 Other laterality molecules, such as Lefty1, Flectin, hLAMP, and Fibrillin-2, also display L-R asymmetric expression and may participate in the regulation of heart laterality.23,24,30,31 Perturbation of expression of these molecules during early chick embryogenesis could result in a laterality defect of the heart. For a complete list of laterality genes and a summary of signaling pathways in L-R determination in several different species, please see a recent review by Mercola and Levin.32

Expression and Regulation of Pitx2 in Early Developing Chick Embryo

The chick Pitx2 gene was cloned and shown to be expressed asymmetrically in the LPM and developing organs in early embryo simultaneously by several laboratories.28,29,33 Two differentially spliced chick Pitx2 isoforms have been isolated that correspond to the mouse and human Pitx2a and Pitx2c.28,29,33-35 The chick Pitx2a and Pitx2c, while differing only by 77 amino acids at the N-terminal region between themselves, show 100% identity within the homeodomain to their mouse and human correspondents at the amino acid level.

In the developing chick embryo, strong Pitx2 expression could be detected at early gastrulation stage (HH-stage 4), with its transcripts localizing symmetrically in the hypoblast and area opaca.33,35 Around HH-stage 7, asymmetric Pitx2 expression initially appears as a small patch restricted to the left LPM, just lateral and anterior to Hensen's node, while strong and symmetric Pitx2 expression is also seen in the head mesenchyme (Fig. 1A,D).33 The asymmetric Pitx2 expression domain in the left LPM then extends both anteriorly and posteriorly, and becomes evident along the entire left LPM by HH-stage 8 (Fig. 1B,E).28,29,36 This asymmetric Pitx2 expression in the left LPM appears slightly later than and overlaps with that of Nodal.14,15,22 At the straight heart tube and looping stages (HH-stages 10-11), Pitx2 expression remains limited to the myocardium of the left sided heart tube and the left vitelline vein (Fig. 1C,F). By stage 15, expression in the heart is only seen in the atrial myocardium. In addition, asymmetric Pitx2 expression is also detected in the primitive gut and its derivatives.28,29,33,36 Of the two chick Pitx2 isoforms, Pitx2c is exclusively expressed in the left LPM, left half of the heart tube, and the head mesoderm. In contrast, Pitx2a transcripts are present in head mesoderm and extraembryonic mesoderm, but are absent in the LPM.35 The asymmetric expression of Pitx2c in the left LPM is also conserved in mouse and Xenopus.37 In contrast, in Zebrafish, Pitx2c only exhibits left-sided expression in the developing diencephalon but Pitx2a shows asymmetric expression in the left LPM.38

Figure 1. Expression of Pitx2 in early developing chick embryo.

Figure 1

Expression of Pitx2 in early developing chick embryo. A, D) Pitx2 expression in the left LPM can be detected as early as HH-stage 7 as a small patch (arrow) (A), as confirmed (arrowhead) by section shown in (D). Pitx2 expression in the head mesoderm is (more...)

The expression pattern and timing of Pitx2 in the LPM suggested that it might be a downstream target of the Shh-Nodal signaling pathway. Indeed, ectopic expression of Shh to the right LPM led to bilateral Pitx2 expression. On the other hand, blockade of Shh activity in the left side of Hensen's node by application of anti-Shh antibody before HH-stage 6 repressed Pitx2 expression in the left LPM (Fig. 2).28,29,33,36 Furthermore, misexpression of Nodal to the right LPM also caused bilateral Pitx2 expression through the LPM.28,29,36 Pitx2 expression is thus regulated through the Shh-Nodal signaling pathway in the developing chick embryo. It was demonstrated in mice that the asymmetric expression of Pitx2 is directly induced by Nodal signaling through the action of the transcription factor FAST and maintained by Nkx2.5.39 In addition to the regulation by Nodal, Activin, another member of TGF-β superfamily, was also able to activate Pitx2 expression in Xenopus embryo.40 However, in chick embryo, activation of Pitx2 in the left LPM by Nodal is mediated by the repression of a zinc finger transcriptional repressor SnR.41 SnR is initially expression bilaterally, and then restricted to the right LPM when Nodal begins to be expressed in the left LPM.27 Repression of SnR expression by anti-sense oligonucleotides could result in ectopic Pitx2 in the right LPM.41

Figure 2. Regulation of Pitx2 by Shh in chick embryo.

Figure 2

Regulation of Pitx2 by Shh in chick embryo. A) A HH-stage 9 embryo which received a bead (b) soaked with Shh protein at stage 5 exhibits bilateral Pitx2 expression in the LPM. Arrow points to the ectopic Pitx2 expression in the right LPM. B) A HH-stage (more...)

Retinoic acid (RA) is known to influence cardiac looping in vertebrate embryos by regulating expression of genes involved in L-R patterning.42-45 RA has been demonstrated to be required for the normal expression of Pitx2 in the left LPM in developing avian embryos. Either excess or deficiency in the retinoid signal leads to abnormal Pitx2 expression.43,45

Down-regulation of Pitx2 was observed in the retinoid-deficient quail embryo that exhibits randomization of heart looping direction.45 Similarly, application of RA antagonist to the left side of Hensen's node represses Pitx2 expression in the LPM, while application of exogenous RA to the right side induces ectopic Pitx2 in the right LPM.43 Paralleled with the repression or ectopic expression of Pitx2 regulated by RA signal is the aberrant expression of Nodal and Lefty-1 but not Shh, indicating that the effect of RA on Pitx2 expression may be mediated through Lefty-1 and Nodal in a pathway downstream or in parallel to Shh.43

Normal Pitx2 expression in the left LPM also depends on the activity of N-cadherin that is distributed asymmetrically in Hensen's node, with restriction to the right side. Blocking of N-cadherin function with anti-N-cadherin antibody at HH-stage 3 to 4 modified Pitx2 expression to either a bilateral or reversed pattern in the LPM.19 It was suggested that N-cadherin might mediate a pathway in parallel to that mediated by Nodal, since blocking N-cadherin function did not perturb Nodal expression in the developing chick embryo.19 In contrast, another study demonstrated application of a blocking anti-N-cadherin antibody to the right side of Hensen's node resulted in ectopic expression of Nodal to the right LPM.21 The right-sided expression of N-cadherin in the node seems to normally antagonize the Shh-independent Wnt signaling pathway which otherwise induces Nodal expression in the right side of the embryo. It appears that Nodal plays a converging role to mediate the regulation of Pitx2 by several independent signaling pathways.

Function of Pitx2 in the Regulation of Heart Looping Direction

In vitro assays have demonstrated that Pitx2 encodes a transcription activator, with the transactivation domain mapped to its C-terminus.35,46,47 As a transcription factor downstream from the Shh-Nodal signaling pathway, Pitx2 products may interpret and execute the L-R developmental program. The function of Pitx2 in the regulation of heart looping in developing chick embryo has been examined by both loss-of-function and gain-of-function approaches. Misexpression of Pitx2 via infection of RCAS-retrovirus carrying Pitx2 gene to the right side LPM randomized heart looping directions (Fig. 3B).28,29,35 Interestingly, when ectopically expressed in the right LPM, both Pitx2a and Pitx2c equally resulted in randomization of the direction of heart looping. This was explained by the fact that an identical C-terminus containing the transactivation domain is present in both isoforms that may activate the same set of downstream genes or execute similar downstream functions.35 The capability of Pitx2 to direct the situs of heart looping was verified by misexpressing Pitx2 to the right LPM while blocking the endogenous Pitx2 in the left LPM with anti-Shh antibody. Reversion in heart looping direction was seen in such treated embryos.28 The importance of Pitx2 in the regulation of heart looping direction in the chick was further corroborated by loss-of-function studies. Elimination of Pitx2c in the left LPM by anti-sense oligonucleotide treatment or by misexpression of a dominant negative form of Pitx2c to the left LPM randomized the direction of heart looping (Fig. 3C).35 These studies provided unambiguous evidence for Pitx2 as a critical effector downstream from the Shh-Nodal signaling pathway to regulate heart looping directionality in the chick. However, it was also observed that asymmetric Pitx2 expression is not always coupled with the heart looping direction in chick embryos. Abnormal heart looping still occurred even if Pitx2 in the left LPM remained unaltered.19,41 Furthermore, Pitx2-deficient mice do not exhibit a looping defect, although severe laterality defects were observed in other organs (see the following chapter for details on the role of Pitx2 in mouse heart development).48-52 It was thus suggested that other equally important genes are also involved in asymmetric development of the heart.53

Figure 3. Misexpression of Pitx2 in chick embryo leads to randomization of heart looping direction.

Figure 3

Misexpression of Pitx2 in chick embryo leads to randomization of heart looping direction. A) A control embryo at HH-stage 11 exhibits left sided looping of the heart (arrow). B) A HH-stage 11 embryo which was infected with RCAS-Pitx2c on the right LPM (more...)

Being a transcription activator, Pitx2 may control heart looping by regulating the expression of downstream gene(s). It was speculated that Pitx2 does so through contractile proteins based on the observation of Pitx2 expression in the muscular layers in the heart and gut and in the sites where muscle differentiation occurs.28,54 Recently, one putative downstream target of Pitx2, procollagen lysyl hydroxylase (Plod)-2 has been identified by chromatin precipitation in mice.55 Members of the Plod gene family encode for enzymes that hydroxylate lysines in collagens. The hydroxylysine residues provide more stable attachment sites for carbohydrate units.Pitx2 was shown to coexpress with Plod-1 and Plod-2 in several embryonic and adult mouse tissues, including the heart, lung, brain, and skeletal muscle.55 Mutations in PLOD-1 are often associated with Ehlers-Danlos syndrome, kyphoscoliosis type (EDVI) patients who share several characteristics with the Axenfeld-Rieger syndrome patients.55 Examination of Plod/PLOD expression in Pitx2 mutant mice or Axenfeld-Rieger syndrome patients would validate Plod genes as downstream targets of Pitx2. Evidence derived from studies in chick embryo indicates that Pitx2 may control heart looping by modulating the expression of the downstream morphoregulatory ECM molecule flectin in the heart.56 Flectin is an extracellular matrix molecule that shows L-R asymmetric localization during heart looping in mice and chick, with its expression predominantly in the left heart field and heart tube.31,57 Blocking of flectin activity by a monoclonal antibody against flectin causes cardiac laterality defect which may result from perturbation of mechanical interactions between flectin and other components of the extracellular matrix.56 In those chick embryos that carried misexpression of Pitx2c to the right LPM or were treated with antisense oligonucleotide to Pitx2c and showed leftward heart looping, flectin expression pattern was reversed. These embryos exhibited a predominant flectin expression in the right mesocardial fold and right side of the heart extending from the fold region.56 However, the regulation of flectin byPitx2 is unlikely to be directly because flectin is also normally expressed in the right sided heart field and heart tube wherePitx2 is absent. Although the specific biochemical interactions or cell signaling mediated by flectin are elusive, flectin apparently functions downstream of Pitx2 and participates in morphoregulatory pathways involved in coordinating heart looping.

Heart looping is an intricate process involving multiple interactions between numerous factors. Significant progress has been made in the past few years in identifying molecules and in establishing signaling cascades involved in the regulation of heart looping. However, at the present time, there is no model that can integrate the molecular data into the biomechanics of heart looping. The mechanisms of Pitx2 in regulating the cellular or biomechanical processes that drive dextral heart looping remains unknown. Pitx2 is undoubtedly not the only factor, but a central mediator in the regulation of heart looping. Identification of Pitx2 downstream target genes and understanding of their associated cellular mechanisms including cell adhesion, migration, proliferation, and apoptosis would definitely provide mechanistic insights into this crucial process during cardiac morphogenesis.


The research discussed here from the authors' laboratory has been supported by grants from the American Heart Association and National Institutes of Health.


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