The heart is the first functional organ to form during embryonic development as it is essential to maintain a sufficient blood supply to support the growing embryo. Likewise, a correct vascular network is required to efficiently circulate blood throughout the embryo. Failure of the heart or the great vessels (the main large vessels that bring blood in and out of the heart) to form correctly, leads to defects in the newborn which can be life-threatening. Congenital cardiovascular malformations (CCVM) are of great clinical importance as they are the most common type of birth defect, affecting 9 in every 1000 live births (Hoffman and Kaplan, 2002). The main cardiovascular defects found in patients with CCVM involve anomalous blood flow between cardiac chambers or between the chambers and cardiac outflows (aortic and pulmonary arteries). Anomalies specifically affecting the great arteries account for a significant proportion of CCVM and are derived from failure during the formation or remodelling of the pharyngeal arch arteries in the developing embryo.
The formation of the heart starts at around embryonic day 15 in humans (Carnegie stage 7, CS7) which is equivalent to embryonic day (E) 7.5 in the mouse when a pool of cardiac precursor cells fuse in the midline of the embryo and then form a beating linear tube. As the tube grows and elongates by proliferation of the cardiac precursors, it loops to the right and the formation of the ventricles and atria starts, subsequently forming the four-chambered heart. The single-channelled outflow tract of the heart is then remodelled and septated into the ascending aorta and pulmonary trunk, arising from the left and right ventricles respectively (reviewed in (Anderson et al., 2003).
During early embryogenesis the single outflow tract channel of the heart is connected to the aortic sac, a primitive cavity ventral to the pharyngeal arch arteries (PAA) from which these arise to connect the heart with the dorsal aorta (Congdon, 1922; Hiruma et al., 2002). The PAA are formed within the pharyngeal arches as 5 pairs of bilaterally symmetrical arteries that are subsequently remodelled to form the great arteries, namely the aorta, subclavian and carotid arteries, and the ductus arteriosus.
The pharyngeal arches (Figure 1a) in mammals appear as a transient series of bulges, formed on both sides of the developing embryo below the head (Graham and Smith, 2001). Pharyngeal arches are composed of a mesenchymal core derived from cardiac neural crest cells and pharyngeal mesoderm, surrounded by an external layer of ectoderm and an inner endodermal one (Figure 1b). These arches will form, or contribute to, different tissues such as sensory neurons of the epibranchial ganglia, the endodermal epithelium of the pharynx, and the thyroid, parathyroid and thymus glands. Within the core of each pharyngeal arch, the PAAs are formed (Figure 1c) by the differentiation of mesoderm cells into endothelium to form the vascular wall. There is also a contribution from neural crest cells which differentiate into vascular smooth muscle cells that surround and support the developing blood vessels (Kirby and Waldo, 1995). The PAAs then undergo a complex remodelling process to form the final asymmetrical structure of the great arteries seen in adults (Congdon, 1922; Hiruma et al., 2002) (Figure 2).
The PAAs are formed sequentially to connect the aortic sac with the dorsal aorta. The 1st and 2nd PAAs persist only for a short period of time and then regress almost completely with their remnants contributing to parts of the maxillary and stapedial arteries. The 3rd right and left PAAs will form parts of the right and left common carotid arteries, respectively, while the right 4th PAAs will persist as part of the proximal right subclavian artery and the left 4th will form the central part of the aortic arch. Although the proximal part of the 6th PAA forms the proximal region of the pulmonary arteries, the rest of the right 6th PAA regresses completely while the left distal part of the 6th PAA forms the ductus arteriosus, a connection between the pulmonary artery and the descending aorta that persists during foetal life to allow blood to bypass the non-functional lungs and then closes directly after birth.
For a better understanding of the steps involved in this complex remodelling process, we have built 3D reconstructions of the development of the pharyngeal arch arteries from a series of human embryos at different stages (CS13 to CS17) imaged by high resolution episcopic microscopy (Weninger et al., 2006) to visualize the main events occurring during the remodelling of the PAAs (Figure 3).
As can be seen in the 3D models in Figure 3, at CS13 (28-32 days; E9.5 in mouse) the 3rd and 4th PAAs are clearly visible connecting the aortic sac with the dorsal aorta, while the 6th (highlighted in yellow) is just forming, which can be better appreciated in the lateral views (Figure 2a’ and 2a’’). At this stage the 1st and 2nd PAA have regressed. By CS14 (31-35 days, E10.5 in mouse; Figure 2b-b’’) the 6th pair of arteries are completely formed and can be seen connecting the aortic sac with the dorsal aorta, and the pulmonary arteries start to arise by vasculogenesis from the proximal region of the 6th PAA in a caudal direction parallel to the dorsal aorta. The carotid duct, the portion of the dorsal aorta between the 3rd and 4th PAAs, starts to regress while the aortic sac is completely septated into the aorta and pulmonary trunk by this stage. At CS16 (37-42 days; E11.5 in mouse; Figure 2d-d’’) the carotid duct appears much thinner and the distal portion of the right 6th artery has started to regress. By CS17 (42-44 days; E12.5 in mouse; Figure 2e-e’’) the carotid duct and the distal part of the right 6th artery have regressed almost completely while the 3rd PAA appear thinner as they undergo remodelling. The dorsal aorta is remodelled as well (Figure 2e-e’’), as the left portion enlarges and forms the distal aortic arch and the descending aorta (Figure 2e’’), whereas the right dorsal aorta regresses almost completely (Figure 2e-e’), except for the portions opposite the 4th right PAA, where its remnants will contribute to the right subclavian artery. Most of the subclavian arteries are formed from the 7th dorsal intersegmental arteries, which develop and migrate in a cephalic direction.
Although the existence of a fifth pair of PAAs is still a matter of debate, evidence suggests that they exist only briefly and it is not yet known whether they make any contribution to the final structure of the great arteries (Bamforth et al., 2013).
The formation of the PAAs is evolutionarily conserved among vertebrates (reviewed in (Kardong, 2008), although clear differences are observed among different species. For example, in the zebrafish, only two of the initial six PAA are remodelled and the other four persist. Another example is the remodelling of the PAA in chick embryos where the right 4th PAA forms the aortic arch instead of the left as in humans and mice. However, the formation of a set of bilaterally symmetrical arteries connecting the primitive heart with the paired dorsal aorta, which are then remodelled into the great vessels to correctly bring blood in and out of the heart, occurs overall in the same fashion in all mammals. Imaging studies have revealed that the formation and patterning of the PAAs in mouse (Bamforth et al., 2013; Hiruma et al., 2002) closely resembles the process that occurs in humans (Bamforth et al., 2013; Congdon, 1922), as both present with 5 pairs of pharyngeal arches in the developing embryo and form a similar structure of the great arteries in adults. Although the timing slightly differs due to the short pregnancy in mice, the remodelling process occurs in the same way. Additionally, the genetics underlying this process in mice also appears to be similar to humans, making the mouse a good model for the study of PAA development in CCVM.
The ability to selectively manipulate the mouse genome to model human disease has provided valuable insight into the genetic processes underlying human developmental disorders. The use of transgenic mouse models to study the development of the PAAs and malformations affecting the great arteries has provided key information to understanding the pathology of PAA-related abnormalities (Kameda, 2009; Scambler, 2010). This has been the case for 22q11 deletion syndrome.
22q11 deletion syndrome (22q11DS, also known as DiGeorge Syndrome, velo-cardio-facial syndrome, conotruncal anomaly face syndrome) is the most common micro-deletion syndrome occurring in humans, affecting 1 in every 4000 live births (Scambler, 2010). Affected individuals display a wide variety of abnormalities including craniofacial dysmorphology, cleft palate, immune deficiency, cardiovascular defects and mental retardation. About 75% of patients with 22q11DS have cardiovascular abnormalities such as ventricular septum defects, persistent truncus arteriosis, Tetralogy of Fallot, retro-esophageal right subclavian artery and interrupted aortic arch type B. Importantly, approximately 50% of patients with interrupted aortic arch have a 22q11DS diagnosis. The abnormal regression of the left 4th PAA, or a complete failure of its formation, leads to an interrupted aortic arch, a disruption in the connection between the ascending and descending aorta, consequently breaking off the supply of oxygenated blood to the rest of the body upon closure of the ductus arteriosus after birth.
Patients with 22q11DS harbour either a 3Mb or 1.5 Mb deletion on chromosomal band q11.2 on chromosome 22. Within this region, more than 30 genes are commonly deleted, but TBX1 is thought to be the main gene involved in causing the 22q11DS cardiovascular phenotype (Jerome and Papaioannou, 2001; Lindsay et al., 2001; Merscher et al., 2001).
TBX1 belongs to a family of T-box binding transcription factors that play key roles during embryonic development for the formation of many tissues. TBX1 has been shown to be particularly important for cardiovascular development, as deletion of the Tbx1 gene in transgenic mouse models leads to cardiovascular defects similar to those seen in 22q11DS patients (Jerome and Papaioannou, 2001; Lindsay et al., 2001; Merscher et al., 2001). In this context, Tbx1-null embryos present with abnormal patterning of the pharyngeal arches where the 1st and 2nd arches are hypoplastic and the 3rd, 4th and 6th pouches are absent. Moreover, the PAAs are not formed in Tbx1-null embryos and a single artery connects the aortic sac with the dorsal aorta instead, and all pups die soon after birth. Although the majority of Tbx1 heterozygous (Tbx1+/-) mice are viable, Tbx1+/- embryos can display 4th PAA-derived defects (Figure 4) including retro-esophageal right subclavian artery, cervical aortic arch, cervical right subclavian artery, and interrupted aortic arch, which resemble the PAA anomalies seen in 22q11DS human patients. Tbx1+/- mice are therefore considered a good clinical model of 22q11DS. Examination of the developing PAA system by injection of india ink into the E10.5 embryo heart reveals that Tbx1+/- embryos have 4th PAA defects at this stage (Figure 5), which potentially explains abnormalities such as the abnormal right subclavian artery and interrupted aortic arch, as both structures are derived from the 4th PAA, and both anomalies are common in 22q11DS patients. However, the incidence of 4th PAA defects seen around mid-embryogenesis in Tbx1+/- embryos is reduced in older embryos, where a smaller proportion of embryos exhibit defects in the great arteries than would be expected from the incidence detected at E10.5 (Calmont et al., 2009; Lindsay and Baldini, 2001; Randall et al., 2009; Ryckebusch et al., 2010). This indicates that some form of recovery occurs during the remodelling of the PAAs (Lindsay and Baldini, 2001; Papangeli and Scambler, 2012).
Tbx1 is expressed in the ectoderm, mesoderm and endoderm of the pharyngeal arches but not in the neural crest cells (Chapman et al., 1996; Zhang et al., 2005), although loss of Tbx1 affects cardiac neural crest cell migration (Calmont et al., 2009; Zhang et al., 2005; Zhang et al., 2006). Tbx1 expression is induced and sustained by Sonic hedgehog (Shh) expression in the pharyngeal endoderm (Garg et al., 2001) which in turn promotes the expression of the Forkhead transcription factors Foxa2, Foxc1 and Foxc2 which directly promote Tbx1 expression (Hu et al., 2004; Yamagishi et al., 2003).
The required expression of Tbx1 in the different tissues of the pharyngeal arches for correct arch artery development has been shown using conditional-knockout models to delete Tbx1 specifically from the mesoderm (Zhang et al., 2006), endoderm (Arnold et al., 2006) and ectoderm (Calmont et al., 2009; Randall et al., 2009). In this context, conditional deletion of Tbx1 from the mesoderm or the endoderm causes abnormal patterning of the pharyngeal arches, subsequently affecting the development of the PAA, and displaying abnormalities similar to those seen in the global Tbx1-null embryos. Conditional deletion of Tbx1 from the pharyngeal surface ectoderm does not affect the patterning of the pharyngeal arches but affects the formation of the 4th PAA, resembling the phenotypes seen in Tbx1+/- embryos. Furthermore, Tbx1 expression in the pharyngeal ectoderm was shown to be required to control cardiac neural crest cell migration through Gbx2 expression (Calmont et al., 2009) which could explain the abnormal development of the 4th PAA in ectoderm-Tbx1-null embryos due to the reduced number of cardiac neural crest cells in the pharyngeal arches.
Timed conditional inactivation of Tbx1 revealed its requirement at a precise time frame between E7.5 and E8.5 for correct PAA development, whereas septation of the outflow tract requires Tbx1 expression between E8.5 and E9.5 (Xu et al., 2005). Later deletion of Tbx1 at E11.5 or E12.5 affects only the formation of other tissues (i.e. thymus, secondary palate) but not the heart or the PAA.
Tbx1 mRNA expression levels are also critical for correct PAA development as has been shown using hypomorphic alleles of Tbx1 (Zhang and Baldini, 2007). Reduced levels of Tbx1 mRNA mainly affects the development of the 4th PAAs and the septation of the outflow tract, and the severity of the cardiovascular defects observed increase with further reductions in the levels of Tbx1 expression. Additionally, over-expression of Tbx1 in mice with extra copies of the gene leads to cardiovascular abnormalities similar to those seen in Tbx1+/- mice (Liao et al., 2004).
The cardiovascular defects seen in Tbx1-null mice are largely due to a significant reduction in the proliferation of second heart field cells, where Tbx1 is also expressed. Such reduction in proliferation is caused mainly by down-regulation of Fgf8, a direct target of Tbx1 (Vitelli et al., 2002). Further studies have found that Tbx1 interacts with Six1-Eya1 transcription factors which in turn regulate Fgf8 expression, and loss of either Six1, Eya1 or both lead to cardiovascular defects similar to those in Tbx1 mutant mice and 22q11DS patients (Guo et al., 2011). Moreover, proliferation of second heart field cells is also affected by down-regulation of Wnt5a in Tbx1-null embryos as Tbx1 is required to interact with Baf60a/Smarcd1 chromatin remodelling factors to promote Wnt5a expression (Chen et al., 2012).
It has also been suggested that Tbx1 may promote proliferation of second heart field cells by directly interacting with Smad1, and therefore preventing Bmp4 signalling (Fulcoli et al., 2009).
However, Tbx1 does not only regulate heart and PAA development by promoting proliferation of progenitor cells, but also by regulating their differentiation. Tbx1 has been found to regulate Smad7 expression by binding directly to T-box elements within the Smad7 gene and further regulating Tgfβ signalling to control vascular smooth muscle differentiation, which is essential for PAA remodelling (Papangeli and Scambler, 2012).
Furthermore, expression of many other genes is affected by loss of Tbx1, as demonstrated by microarray analysis of Tbx1-null embryo tissue (Ivins et al., 2005; Liao et al., 2008).
The central role of TBX1 and its multiple genetic interactions and intersections with different signalling pathways could be the basis for the wide spectrum of phenotypes seen in 22q11DS patients, where mutations in other genes directly or indirectly interacting with TBX1 may determine the phenotype.
FIGURES AND LEGENDS
Figure 1. The human pharyngeal arches. Coronal section of the pharyngeal arches, obtained by high resolution episcopic microscopy of a Carnegie stage 15 human embryo. (a) The 3rd, 4th and 6th pharyngeal arches (PA) are labelled. (b) The tissue components that comprise the pharyngeal arches; the inner endoderm layer, the external layer of ectoderm, the mesoderm, the mesenchymal core and the arch artery are indicated. (c) The pharyngeal arch arteries have been reconstructed in 3D. Each artery is found within the centre of each pharyngeal arch and connects the aorta (ao) and pulmonary trunk (pt), which is septated by this stage.
Figure 2. Remodelling of the pharyngeal arch arteries. (a) Depiction of the initial symmetrical structure of the paired PAA connecting the aortic sac with the paired dorsal aorta. (b) Structure of the great arteries in the adult heart. The symmetric PAA undergo a complex remodelling process in which most of the right dorsal aorta regresses (dotted lines) as well as the carotid duct on both sides. The 3rd PAA (yellow) forms the common carotid arteries. The right 4th (orange) forms part of the right subclavian artery while the left 4th forms the central part of the aortic arch. The right 6th (purple) regress almost completely, while the distal part of the left 6th forms the ductus arteriosus (da), which closes (white dotted lines) after birth. The pulmonary arteries arise from the proximal part of the 6th PAA. The 7th intersegmental artery forms the left subclavian artery and the distal part of the right subclavian artery following remodelling and regression of the dorsal aorta. Ao, ascending aorta; BCA, brachiocephalic artery; dAo, dorsal aorta; da, ductus arteriosus; ISA, intersegmental artery; LCC, left common carotid; LSA, left subclavian artery; pa, pulmonary arteries; PT, pulmonary trunk; RSA, right subclavian artery; RCC, right common carotid.
Figure 3. 3D reconstruction of data sets from a series of human embryos at different Carnegie Stages (CS13 to CS17) imaged by high resolution episcopic microscopy showing the main changes occurring (in yellow) during the development of the PAAs from frontal, right and left views. PAA are numbered; ao, aorta; cd, carotid duct; pa, pulmonary arteries; pt, pulmonary trunk. Figure courtesy of Dr Simon Bamforth.
Figure 4. 3D reconstruction of MRI data sets from E15.5 wildtype (a) and Tbx1+/- (b) mouse embryos imaged by magnetic resonance imaging (Bamforth et al., 2012) showing some of the defects (indicated in yellow) seen in Tbx1+/- embryos such as cervical right subclavian artery (CoRSA), ventricular septal defect (VSD) and interruption of the aortic arch (IAA).
Figure 5. Early PAA development as visualised by intracardiac ink injections in wildtype (a-a’) and Tbx1+/- (b-b’) embryos at E10.5. In wildtype embryos (a-a’), the 3rd, 4th and 6th PAA are clearly patent to ink whereas in Tbx1+/- (b-b’) embryos the right 4th PAA is hypoplastic and the left 4th PAA is non-patent to ink and therefore presumed to be absent.
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ABL would like to thank the Development, Anatomy and Pathology Working Group of the European Society of Cardiology for granting him the Pexieder award (Amsterdam, 2012), and Dr. Simon Bamforth, Dr. Helen Phillips and Dr. Helen Arthur for their great support during the project and their helpful comments on this manuscript.
This research is supported by a Scholarship from the National Science Council of Mexico (CONACyT) to ABL, and a British Heart Foundation Intermediate Basic Science Research Fellowship awarded to Dr. Simon Bamforth.
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