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Keywords:

  • anterior/secondary heart field;
  • conotruncal heart defects;
  • heart development;
  • lineage;
  • outflow tract

ABSTRACT

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. DYNAMIC MOVEMENT OF HEART PROGENITOR CELLS DURING FORMATION OF THE PRIMITIVE HEART TUBE
  5. CONOTRUNCAL REGION IS ADDED TO THE PRIMITIVE HEART TUBE FROM BOTH THE PHARYNGEAL AND SPLANCHNIC MESODERM DURING LOOPING
  6. SIGNALING REGULATING THE FORMATION OF THE OUTFLOW TRACT FROM THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD
  7. ABNORMAL DEVELOPMENT OF THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD CAUSES CONOTRUNCAL HEART DEFECTS
  8. ANTERIOR HEART FIELD/SECONDARY HEART FIELD DEFECTS AND 22Q11.2 DELETION SYNDROME
  9. ALTERED DEVELOPMENT OF ANTERIOR HEART FIELD/SECONDARY HEART FIELD MIGHT CAUSE TRANSPOSITION OF THE GREAT ARTERIES
  10. INTERACTIONS BETWEEN THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD AND CARDIAC NEURAL CREST
  11. CONCLUSIONS
  12. ACKNOWLEDGMENTS
  13. REFERENCES

Abnormal heart development causes various congenital heart defects. Recent cardiovascular biology studies have elucidated the morphological mechanisms involved in normal and abnormal heart development. The primitive heart tube originates from the lateral-most part of the heart forming mesoderm and mainly gives rise to the left ventricle. Then, during the cardiac looping, the outflow tract is elongated by the addition of cardiogenic cells from the both pharyngeal and splanchnic mesoderm (corresponding to anterior and secondary heart field, respectively), which originate from the mediocaudal region of the heart forming mesoderm and are later located anteriorly (rostrally) to the dorsal region of the heart tube. Therefore, the heart progenitors that contribute to the outflow tract region are distinct from those that form the left ventricle. The knowledge that there are two different lineages of heart progenitors in the four-chambered heart provides new understanding of the morphological and molecular etiology of conotruncal heart defects.


INTRODUCTION

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. DYNAMIC MOVEMENT OF HEART PROGENITOR CELLS DURING FORMATION OF THE PRIMITIVE HEART TUBE
  5. CONOTRUNCAL REGION IS ADDED TO THE PRIMITIVE HEART TUBE FROM BOTH THE PHARYNGEAL AND SPLANCHNIC MESODERM DURING LOOPING
  6. SIGNALING REGULATING THE FORMATION OF THE OUTFLOW TRACT FROM THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD
  7. ABNORMAL DEVELOPMENT OF THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD CAUSES CONOTRUNCAL HEART DEFECTS
  8. ANTERIOR HEART FIELD/SECONDARY HEART FIELD DEFECTS AND 22Q11.2 DELETION SYNDROME
  9. ALTERED DEVELOPMENT OF ANTERIOR HEART FIELD/SECONDARY HEART FIELD MIGHT CAUSE TRANSPOSITION OF THE GREAT ARTERIES
  10. INTERACTIONS BETWEEN THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD AND CARDIAC NEURAL CREST
  11. CONCLUSIONS
  12. ACKNOWLEDGMENTS
  13. REFERENCES

Congenital heart defects (CHD) are diagnosed in 19–75 per 1000 liveborn infants. The incidence of the moderate and severe forms of CHD is approximately 6/1000 live-births, and the incidence of conotruncal heart defects is 12–14% in all CHD (Hoffman and Kaplan 2002). Despite the importance of the etiology of life-threatening CHD, little is known about the molecular and morphological mechanisms involved in CHD. Recent rediscovery of a second lineage of heart forming cells in the pharyngeal/splanchnic mesoderm that reside anteriorly (rostrally) to the dorsal region of the primitive heart tube has led us to reconsider cardiogenesis and the morphological mechanisms leading to CHD (Kelly et al. 2001; Mjaatvedt et al. 2001; Waldo et al. 2001). The purpose of the present review is to better understand the development of the heart forming regions and to consider the mechanisms that lead to conotruncal heart defects.

DYNAMIC MOVEMENT OF HEART PROGENITOR CELLS DURING FORMATION OF THE PRIMITIVE HEART TUBE

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. DYNAMIC MOVEMENT OF HEART PROGENITOR CELLS DURING FORMATION OF THE PRIMITIVE HEART TUBE
  5. CONOTRUNCAL REGION IS ADDED TO THE PRIMITIVE HEART TUBE FROM BOTH THE PHARYNGEAL AND SPLANCHNIC MESODERM DURING LOOPING
  6. SIGNALING REGULATING THE FORMATION OF THE OUTFLOW TRACT FROM THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD
  7. ABNORMAL DEVELOPMENT OF THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD CAUSES CONOTRUNCAL HEART DEFECTS
  8. ANTERIOR HEART FIELD/SECONDARY HEART FIELD DEFECTS AND 22Q11.2 DELETION SYNDROME
  9. ALTERED DEVELOPMENT OF ANTERIOR HEART FIELD/SECONDARY HEART FIELD MIGHT CAUSE TRANSPOSITION OF THE GREAT ARTERIES
  10. INTERACTIONS BETWEEN THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD AND CARDIAC NEURAL CREST
  11. CONCLUSIONS
  12. ACKNOWLEDGMENTS
  13. REFERENCES

At the pregastrula stage of amniotes, the embryos consist of two concentric epithelial layers, the epiblast on the dorsal side, and the hypoblast on the ventral side. Our body develops from the epiblast layer of the blastula embryo. Fate map analysis using fluorescent dye or explantation germ layer experiments in avian embryos, which are amniotes and consist of disk-like flat germ layers similar to the human embryonic disc, shows that prospective heart cells reside in the posterior lateral region of the epiblast layer (red and blue dots in Fig. 1A; Hatada and Stern 1994; Yatskievych et al. 1997; Ladd et al. 1998; Matsui et al. 2005). Before the onset of gastrulation, prospective heart cells move to the anterior region of the posterior half of the epiblast midline, where the primitive streak will soon develop (arrows in Fig. 1A,B).

image

Figure 1. Two sources of heart progenitor cells contribute to form the four-chambered heart. (A) At the blastula stage, prospective heart cells reside in the posterior–lateral region of the epiblast (blue and red dots). At the onset of gastrulation, heart progenitor cells migrate to the region where the anterior primitive streak develops (arrows). (B) In the early gastrula, prospective heart cells reside in the anterior primitive streak in an anterior–posterior sequence (blue and red dots). Later, the prospective heart cells migrate anterolaterally to form the heart mesoderm (arrows). (C) In the late gastrula stage (ventral view), the heart forming mesoderm is developed in the visceral mesoderm of the pericardial coelom (red and blue dots). Due to the formation of the foregut pocket (FP), the left and right heart forming regions move to the midline to fuse (arrows). The lateral-most cells in the heart forming region mainly give rise to the left ventricle (red dots), whereas the medial region forms the outflow tract (OFT) and right ventricle (blue dots). (D) The primitive heart tube is developed from the lateral-most part of the heart forming mesoderm (red dots). The visceral mesoderm behind the primitive heart tube (blue dots) contains future heart regions, including the OFT, the right ventricle, the atrioventricular canal and the atria. (E) During heart looping, the OFT is developed from the anterior heart field (AHF) and the secondary heart field (SHF) in the pharyngeal and splanchnic mesoderm (blue dots in AHF/SHF). Heart progenitors in the caudal splanchnic mesoderm of the pericardial coelom contribute to the atrioventricular canal and the atria. (F) Two sources of progenitors are known in the four-chambered heart: the OFT originates from the medial region of the heart forming mesoderm (blue dots in C), while the LV arises from its lateral-most region (red dots in C). In contrast, the RV, the atrioventricular canal and the atria are derived from the entire heart forming mesoderm (blue and red dots in C). A and B, dorsal view; C-D, ventral view; AHF, anterior heart field; FP, foregut pocket (anterior intestinal portal); LA, left atrium; LV, left ventricle; OFT, outflow tract; PS, primitive streak; RA, right atrium; RV, right ventricle; SHF, secondary heart field.

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During the early primitive streak stage, prospective heart cells, including those of the endocardium, the myocardium and the epicardium, reside in the rostral half of the primitive streak in an anterior–posterior (rostro–caudal) sequence; that is, the cells that will contribute to the outflow tract (OFT) and right ventricle (RV) are included in an anterior region of the anterior half of the primitive streak (blue dots in Fig. 1B), whereas the left ventricle (LV), the atria, and the sinus venosus forming cells are located in the posterior region of the anterior half of the primitive streak (red dots in Fig. 1B; Garcia-Martinez and Schoenwolf 1993). During gastrulation, prospective heart cells ingress into the primitive streak, and thereafter migrate anterolaterally to form the anterior lateral plate mesoderm (arrows in Fig. 1B; Yang et al. 2002; Chuai et al. 2006). Later, the anterior lateral plate mesoderm splits into the dorsal somatic and ventral splanchnic (visceral) mesoderm, resulting in the formation of the pericardial coelom (cavity). At this time, prospective heart cells are restricted to the splanchnic (visceral) mesoderm and constitute the heart forming mesoderm (Linask 1992). Cell tracing experiments have shown that the lateral-most cells in the heart forming mesoderm are incorporated into the atria and the LV (red dots in Fig. 1C), whereas the mediocaudally located progenitor cells are incorporated mainly into the OFT and RV (blue dots in Fig. 1C). In association with the formation of the foregut pocket (anterior intestinal portal; FP in Fig. 1C, D), the heart fields invert along the anterior–posterior (rostro–caudal) axis of the coelom (120–130° in chicks and 180° in humans; arrows in Fig. 1C), bend ventrally, and fuse with each other to form a “myocardial trough,” which is contiguous with the non-cardiac splanchnic mesoderm across the dorsal mesocardium (Moreno-Rodriguez et al. 2006; Abu-Issa and Kirby 2008). Later, the dorsal mesocardium is broken down to generate the primitive heart tube; therefore, it connects with the artery at the anterior pole (OFT) and with the vein at the venous pole (inflow tract). The primitive heart tube contains the future LV, the atrioventricular canal, the atria, and some RV lineage cells (red dots in Fig. 1D), but not the OFT. Surgical deletion of the midline region of the endoderm results in a bilateral heart (cardiac bifida) (Moreno-Rodriguez et al. 2006), and Gata4-mutants affect endoderm development, thereby disrupting heart tube formation, leading to cardia bifida (Narita et al. 1997; Reiter et al. 1999). Therefore, an endoderm effect, the formation of the foregut pocket, appears to be crucial to controlling the migration of the left and right heart fields to the ventral midline during the formation of the primitive heart tube.

In chicks, the segmental polarity of the heart tube is not committed at the primitive streak stage, but rather is established just before the formation of the primitive heart tube (Redkar et al. 2001). Altering the anterior–posterior organization of the precardiac region by grafting affects heart morphogenesis at the primitive heart tube stage but not at earlier stages (Patwardhan et al. 2000). In Meilhac et al. (2003, 2004), retrospective clonal analysis using a lacZ reporter gene targeted to α-cardiac actin revealed clusters of dispersed cells along the venous-arterial axis of the heart tube and the existence of two lineages that segregate from a common precursor, suggesting that the embryonic cardiac regions arise by progressive restriction of cell dispersion rather than pre-pattern formation by lineage specification. Therefore, it is likely that the lineage specification of heart progenitor cells occurs during their migration/movement and is completed immediately before the formation of the primitive heart tube.

CONOTRUNCAL REGION IS ADDED TO THE PRIMITIVE HEART TUBE FROM BOTH THE PHARYNGEAL AND SPLANCHNIC MESODERM DURING LOOPING

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. DYNAMIC MOVEMENT OF HEART PROGENITOR CELLS DURING FORMATION OF THE PRIMITIVE HEART TUBE
  5. CONOTRUNCAL REGION IS ADDED TO THE PRIMITIVE HEART TUBE FROM BOTH THE PHARYNGEAL AND SPLANCHNIC MESODERM DURING LOOPING
  6. SIGNALING REGULATING THE FORMATION OF THE OUTFLOW TRACT FROM THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD
  7. ABNORMAL DEVELOPMENT OF THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD CAUSES CONOTRUNCAL HEART DEFECTS
  8. ANTERIOR HEART FIELD/SECONDARY HEART FIELD DEFECTS AND 22Q11.2 DELETION SYNDROME
  9. ALTERED DEVELOPMENT OF ANTERIOR HEART FIELD/SECONDARY HEART FIELD MIGHT CAUSE TRANSPOSITION OF THE GREAT ARTERIES
  10. INTERACTIONS BETWEEN THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD AND CARDIAC NEURAL CREST
  11. CONCLUSIONS
  12. ACKNOWLEDGMENTS
  13. REFERENCES

Experiments carried out more than 30 years ago suggested that elongation of the heart tube results not only from expansion of the tissue in the heart tube but also from the addition of an extracardiac cell population to both the OFT and inflow tract. Virágh and Challice (1973) demonstrate the continuous transdifferentiation of the non-cardiac splanchnic mesoderm to the myocardium at the venous and arterial poles during mouse cardiogenesis at embryonic day (ED) 8–11. The progressive transdifferentiation of the OFT myocardium from the pharyngeal mesoderm is observed in humans and rats (de Vries 1981). A cell marking investigation of chick cardiogenesis performed by de la Cruz et al. (1977) show that the OFT is added during heart looping between stages 13–22. These investigators suggest that the OFT and inflow tract are derived mainly from cells that reside in the pharyngeal mesoderm and splanchnic mesoderm rather than cell expansion of the primitive heart tube.

In 2001, using experimental manipulation of chick embryos and transgenic approaches in mice, three different groups rediscovered that a (novel) population of cells in pharyngeal and splanchnic mesoderm give rise to the myocardium of the OFT and RV (Kelly et al. 2001; Mjaatvedt et al. 2001; Waldo et al. 2001). Mjaatvedt et al. (2001) show using fate-mapping, ablation and explantation experiments in chicks that the OFT (conus and truncus) is not derived from expansion from the primitive heart tube, but originates from the mesoderm surrounding the aortic sac, which they named the anterior heart field (AHF; AHF in Fig. 1E). Waldo et al. (2001) show that during chick cardiogenesis, the OFT is secondarily added to the straight heart tube from a secondary heart field (SHF) situated at the splanchnic mesoderm beneath the floor of the foregut just caudal to the OFT (SHF in Fig. 1E). These myocardial precursor cells express the heart-specific transcription factors Nkx2.5 and Gata4, but not the Myosin heavy chain. When the precursor cells move to the OFT, they begin to express the HNK1-epitope and then the myosin heavy chain. In mice, a Myosin light chain-nlacZ transgene and cell-tracing experiment showed that the Fgf10 (fibroblast growth factor 10)-positive pharyngeal mesoderm in the AHF contributes to the splanchnic mesoderm, which corresponds to the SHF and, subsequently, to the growth of the OFT and RV (Kelly et al. 2001; Kelly and Buckingham 2002).

The terminology of the rediscovered heart forming field is somewhat confusing (Abu-Issa and Kirby 2007). One group describes the second source of the heart as the “secondary heart field (SHF),” which is located in the splanchnic mesoderm behind the heart (SHF in Fig. 1E, Waldo et al. 2001); whereas others identified an “anterior heart field (AHF),” which includes more of the cranial pharyngeal mesoderm and extends into the pharyngeal arches (AHF in Fig. 1E; Kelly et al. 2001; Mjaatvedt et al. 2001). In the case of mice, lacZ driven by Fgf10 or Fgf8 was expressed in the RV, the OFT, the pharyngeal mesoderm and the splanchnic mesoderm, which is contiguous with the OFT, but was absent from the inflow tract (Kelly et al. 2001; Ilagan et al. 2006). Therefore, both SHF and AHF, in which both Fgf8 and -10 are expressed, contribute to the elongation of the developing OFT of the looped heart during the establishment of the OFT and RV (Fig. 1E).

Cai et al. (2003) report that an LIM homeodomain transcription factor Isl1-null mutant showed severe heart defects involving the OFT, the RV and the atria, which are added to the initial heart tube during looping. At the gastrula stage, Isl1 is expressed in the mediocaudal region of the heart forming mesoderm (blue dots in Fig. 1C), but not in the lateral region. Later, Isl1 is expressed in the pharyngeal and splanchnic mesoderm, which are connected to the OFT, and in the caudal splanchnic mesoderm, which is connected with the inflow tract (extracardiac blue dots in Fig. 1D). Furthermore, clonal analysis using a lacZ-α-cardiac actin locus has suggested that there are two lineages of cardiomyocytes that segregate from a common precursor: the LV and the OFT are derived exclusively from a single lineage, and all other regions possess both lineages (Meilhac et al. 2004). Based on the results of Cai et al. (2003) and Meilhac et al. (2004), Buckingham et al. (2005) propose the “first heart field” (red dots in Fig. 1C), which originates from the lateral region of the heart forming mesoderm and forms the initial heart tube, giving rise to the entire LV, some of the RV, the atrioventricular (AV) canal, and the atria (red dots in Fig. 1D–F), and the “second heart field,” which originates from the mediocaudal region of the heart forming mesoderm and contributes the entire OFT and some of the RV, the atrioventricular canal and the atria (blue dots in Fig. 1C–F). To date, although we do not have any region-specific or lineage-specific marker gene for developing cardiomyocyte, it is evident that both pharyngeal and splanchnic mesoderm (corresponding to AHF and SHF, respectively), that are expressing both Fgf8 and Fgf10, contribute to the OFT. In the present review, the term “AHF/SHF” is used to refer to conotruncal development.

SIGNALING REGULATING THE FORMATION OF THE OUTFLOW TRACT FROM THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. DYNAMIC MOVEMENT OF HEART PROGENITOR CELLS DURING FORMATION OF THE PRIMITIVE HEART TUBE
  5. CONOTRUNCAL REGION IS ADDED TO THE PRIMITIVE HEART TUBE FROM BOTH THE PHARYNGEAL AND SPLANCHNIC MESODERM DURING LOOPING
  6. SIGNALING REGULATING THE FORMATION OF THE OUTFLOW TRACT FROM THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD
  7. ABNORMAL DEVELOPMENT OF THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD CAUSES CONOTRUNCAL HEART DEFECTS
  8. ANTERIOR HEART FIELD/SECONDARY HEART FIELD DEFECTS AND 22Q11.2 DELETION SYNDROME
  9. ALTERED DEVELOPMENT OF ANTERIOR HEART FIELD/SECONDARY HEART FIELD MIGHT CAUSE TRANSPOSITION OF THE GREAT ARTERIES
  10. INTERACTIONS BETWEEN THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD AND CARDIAC NEURAL CREST
  11. CONCLUSIONS
  12. ACKNOWLEDGMENTS
  13. REFERENCES

Fgf10, a target of canonical Wnt signaling in the heart forming mesoderm, was first identified in the AHF/SHF (Kelly et al. 2001); however, Fgf10-null mutant mice have no apparent cardiac defects (Min et al. 1998; Sekine et al. 1999). Another FGF member, Fgf8, is also expressed in the AHF/SHF (Kelly et al. 2001), and Fgf8 hypomorphic mutants have OFT defects, such as double outlet right ventricle (DORV) and persistent trucus arteriosus (PTA) (Abu-Issa et al. 2002; Frank et al. 2002). Detailed analysis of the expression of Fgf8 in AHF/SHF showed that Fgf8 is expressed in the splanchnic mesoderm immediately mediocaudal to the primary heart field at ED 7.75; in the splanchnic mesoderm contiguous with the developing OFT at around ED 8.0–8.5; and in the pharyngeal endoderm and ectoderm close to the AHF, but not in the splanchnic mesoderm or OFT at later stages (Ilagan et al. 2006). Mutant mice (Nkx2.5cre/+; Fgf8flox/−), in which Fgf8 expression is downregulated in the AHF/SHF, showed a truncated OFT/RV, suggesting that Fgf8 is required for AHF/SHF proliferation and survival during elongation of the OFT (Fig. 2; Ilagan et al. 2006). It has also been reported that reduced expression of Fgf8 in the AHF and endoderm results in marked cell death in migrating cardiac neural crest cells in the pharyngeal arches (Abu-Issa et al. 2002; Ilagan et al. 2006). By conditional inactivation of Fgfr1, Fgfr2 and Frs2 (an adaptor protein that links FGF receptor kinases) and overexpression of the FGF antagonist Sprouty-2 in different cell types in the AHF/SHF, the pharyngeal endoderm and the cardiac neural crest, FGF-signaling in the AHF/SHF was shown to be autonomously required for OFT development and its remodeling. In addition, OFT myocardium dysfunction due to reduced FGF signaling in the AHF/SHF blocks the production of the extracellular matrix (cardiac jelly) as well as transforming growth factor-β/bone morphogenetic protein signaling, which are essential for endocardial epithelial–mesenchymal transition as well as invasion of the cardiac neural crest (Fig. 2; Nakajima et al. 2000; Sakabe et al. 2005; Park et al. 2008; Zhang et al. 2008). Therefore, the autocrine loop initiated in the AHF/SHF mesoderm might regulate morphogenesis of the OFT, including elongation, rotation wedging and septation.

image

Figure 2. Signaling pathways controlling the anterior heart field/secondary heart field (AHF/SHF) development. In the AHF/SHF, canonical Wnt and fibroblast growth factor (FGF) signalings play a role in the proliferation of heart progenitor cells. The bone morphogenetic protein (BMP) and non-canonical Wnt pathways (Wnt11) are involved in myocardial specification and differentiation. The OFT expresses BMP and transforming growth factor-β (TGFβ), which contribute to myocardial specification as well as OFT cushion tissue formation. Pharyngeal endoderm derived Shh regulates cellular survival in the AHF/SHF. Left–right specific Pitx2c is expressed in the left splanchnic mesoderm as a means of controlling cellular proliferation.

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Isl1-positive heart progenitors, which reside throughout the anterior and posterior of the splanchnic mesoderm dorsal to the heart, are continuously migrating not only to form anterior segments of the heart (the OFT and RV), but also to contribute to posterior segments (the atria and the AV canal) (Cai et al. 2003). In the hearts of the Isl1-knockout mutants, not only the cardiac looping but also the formation of the OFT, the RV and the atria were all defective. Heart progenitor cells in Isl1-null mutants show defective cellular proliferation and survival, suggesting that Isl1 is required for cardiac morphogenesis via the migration of progenitor cells into the heart. Cai et al also report that the expression of Bmp4, Bmp7, Fgf10, and Wnt11 is reduced in the AHF/SHF of Isl1-null mice, suggesting that the Isl1 in the AHF/SHF is located upstream of these genes (Fig. 2). These observations suggest that the signaling regulating AHF/SHF is similar to that involved in heart specification/differentiation in the first heart field at the gastrula stage (Nakajima et al. 2009).

ABNORMAL DEVELOPMENT OF THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD CAUSES CONOTRUNCAL HEART DEFECTS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. DYNAMIC MOVEMENT OF HEART PROGENITOR CELLS DURING FORMATION OF THE PRIMITIVE HEART TUBE
  5. CONOTRUNCAL REGION IS ADDED TO THE PRIMITIVE HEART TUBE FROM BOTH THE PHARYNGEAL AND SPLANCHNIC MESODERM DURING LOOPING
  6. SIGNALING REGULATING THE FORMATION OF THE OUTFLOW TRACT FROM THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD
  7. ABNORMAL DEVELOPMENT OF THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD CAUSES CONOTRUNCAL HEART DEFECTS
  8. ANTERIOR HEART FIELD/SECONDARY HEART FIELD DEFECTS AND 22Q11.2 DELETION SYNDROME
  9. ALTERED DEVELOPMENT OF ANTERIOR HEART FIELD/SECONDARY HEART FIELD MIGHT CAUSE TRANSPOSITION OF THE GREAT ARTERIES
  10. INTERACTIONS BETWEEN THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD AND CARDIAC NEURAL CREST
  11. CONCLUSIONS
  12. ACKNOWLEDGMENTS
  13. REFERENCES

The fact that the AHF/SHF migrates to the OFT and gives rise to the conotruncal region as well as some parts of the RV reminds us that abnormal migration of the AHF/SHF can cause conotruncal malformations, such as tetralogy of Fallot (TF), double outlet right ventricle (DORV) and transposition of the great arteries (TGA) (Fig. 3). During conotruncal development, the OFT elongates and rotates to establish spirally-oriented pulmonary and systemic channels, in which the RV-pulmonary trunk is positioned on the left ventral side of the LV-aorta (normal OFT in Fig. 3). DiI marking and laser ablation of the SHF in chick showed that the right side of the SHF migrates spirally to the posterior wall of the left side of the OFT, and ablation of the right side of the SHF causes a stunted OFT, resulting in the formation of various types of conotruncal defects, including RV-OFT stenosis or atresia, septal malalignment associated with overriding of the aorta (these are seen in TF, Fig. 3), side-by-side oriented outflow channels and reduced wedging of the aorta to atrioventricular valves (these are seen in DORV, Fig. 3) (Ward et al. 2005). TGA, in which the RV is connected to the right ventrally malpositioned aorta and the LV is connected to the left dorsal pulmonary trunk, is thought to be caused by shortening and reduced rotation of the OFT, straight conotruncal septation and ventriculo-arterial misconnection (TGA, Fig. 3) (Yasui et al. 1995, 1999; Nakajima et al. 1996). The aortico-pulmonary septum is derived from the cardiac neural crest, which migrates to the OFT through the pharyngeal arches as an ectomesenchyme. Ablation of the cardiac neural crest leads to septation defects in the OFT, resulting in PTA (Fig. 3) (Nishibatake et al. 1987). Conotruncal heart defects are considered to be a series of alterations in the AHF/SHF and developing OFT. However, it is uncertain which kinds of spatiotemporally restricted alterations in the AHF/SHF cause particular conotruncal heart defects. Further experiments are necessary to elucidate the mechanisms that lead to malformation-specific alterations.

image

Figure 3. Abnormal development of the AHF/SHF might lead to various conotruncal malformations. The OFT and the right ventricle are derived from the anterior/secondary heart field (AHF/SHF). During OFT development, its elongation, rotation and wedging to atrioventricular valves are important for establishing not only spirally-oriented OFT channels but also appropriate ventricle–arterial alignment. Therefore, alteration of the AHF/SHF causes abnormal development of the OFT, thereby conotruncal heart defects. Cardiac neural crest cells migrated into the pharyngeal arches and OFT interact with the AHF/SHF and contribute to OFT development. Also, cardiac neural crest cells provide the aortico-pulmonary septum. Ao, ascending aorta; AP, aortico-pulmonary; cNC, cardiac neural crest; DORV, double outlet right ventricle; LV, left ventricle; OFT, outflow tract; PA, pulmonary artery; PTA, persistent truncus arteriosus; RV, right ventricle; TF, tetralogy of Fallot; TGA, transposition of the great arteries.

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ANTERIOR HEART FIELD/SECONDARY HEART FIELD DEFECTS AND 22Q11.2 DELETION SYNDROME

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. DYNAMIC MOVEMENT OF HEART PROGENITOR CELLS DURING FORMATION OF THE PRIMITIVE HEART TUBE
  5. CONOTRUNCAL REGION IS ADDED TO THE PRIMITIVE HEART TUBE FROM BOTH THE PHARYNGEAL AND SPLANCHNIC MESODERM DURING LOOPING
  6. SIGNALING REGULATING THE FORMATION OF THE OUTFLOW TRACT FROM THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD
  7. ABNORMAL DEVELOPMENT OF THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD CAUSES CONOTRUNCAL HEART DEFECTS
  8. ANTERIOR HEART FIELD/SECONDARY HEART FIELD DEFECTS AND 22Q11.2 DELETION SYNDROME
  9. ALTERED DEVELOPMENT OF ANTERIOR HEART FIELD/SECONDARY HEART FIELD MIGHT CAUSE TRANSPOSITION OF THE GREAT ARTERIES
  10. INTERACTIONS BETWEEN THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD AND CARDIAC NEURAL CREST
  11. CONCLUSIONS
  12. ACKNOWLEDGMENTS
  13. REFERENCES

22q11.2 deletion syndrome (22q11DS) is an interstitial deletion of chromosome 22 associated with a characteristic phenotype that is clinically recognized as DiGeorge syndrome, velocardiofacial syndrome or conotruncal anomaly face syndrome (CAFS) and is the most common interstitial deletion found in humans, with an incidence of 1 in 4000 live-births. The most common deletion of the 22q11 region involves approximately 3 Mb of genomic DNA containing 30 genes; therefore, 22q11DS is a contiguous gene deletion syndrome (Scambler 2000; Baldini 2005). Characteristic mutual features of 22q11DS are related to the pharyngeal apparatus, such as conotruncal heart defects, craniofacial minor malformations, thymic and parathyroid hypoplasia, and sometimes learning and psychiatric disorders (Scambler 2000; Baldini 2005).

The history of the investigation of the etiology of 22q11DS is exciting. In 1983, Kirby et al. first identified that cardiac neural crest cells contribute to OFT septation as well as the formation of the pharyngeal arch arteries (Kirby et al. 1983); therefore, surgical ablation of the cardiac neural crest was found to cause conotruncal malformations as well as aortic arch anomalies (Huston and Kirby 2007). In 1993, Burn and Takao first demonstrated, by fluorescent in situ hybridization, that patients with CAFS are associated with a haplo-insufficient deletion within 22q11.2 (Burn et al. 1993; Matsuoka et al. 1994). Chromosomal engineering showed that mutant mice suffering from chromosome 16 deletions involving the human 22q11 region (Df1+/−) are affected by congenital cardiovascular malformations seen in human 22q11DS, and several engineered mice carrying deletions in different regions suggested that Tbx1 is the gene responsible for the phenotypic malformations seen in cardiovascular and pharyngeal derivatives (Lindsay et al. 1999; Lindsay 2001). Tbx1 mutant mice were generated by three groups, and the phenotypes of the mutant mice were identical to those of Df1+/− mutant and human 22q11DS (Jerome and Papaioannou 2001; Lindsay et al. 2001; Merscher et al. 2001). Finally, TBX1 mutations have been identified in patients with typical 22q11DS without chromosomal deletions (Yagi et al. 2003). It is now apparent that TBX1 plays a critical role in 22q11DS, but it is still possible that other deleted genes contribute to its phenotype (Baldini 2005).

Tbx1 is a member of the T-domain containing transcription factors, which share a characteristic DNA binding sequence consisting of 200 amino acids and play several roles in organogenesis, including that of the heart (Showell et al. 2004). Tbx1 is expressed in the AHF/SHF, but not in the cardiac neural crest cells in the pharyngeal arches; however, the cardiac neural crest defects in Tbx1 mutant are severe, suggesting that reduction of Tbx1 expression in the AHF/SHF affects neural crest cells (Merscher et al. 2001). Mice hypomorphic for Tbx1 show a lower threshold for Tbx1 in the OFT than pharyngeal arch derivatives, and Tbx1 regulates Fgf8/10 in the AHF/SHF through an autoregulatory loop involving forkhead transcription factors (Hu et al. 2004; Maeda et al. 2006). Tissue-specific ablation of Tbx1 in the AHF/SHF causes severe defects in the OFT as cell proliferation is affected, but pharyngeal segmentation is not affected (Xu et al. 2004). Therefore, reduced expression of Tbx1 and Fgf8/10 might affect cellular proliferation in the AHF/SHF (Fig. 2). In Maeda et al. (2006), lineage tracing experiments using a Cre transgene under the control of a Tbx1 regulatory element suggested that Tbx1 is not expressed in the entire AHF/SHF but in the right-sided OFT, which might give rise to the sub-pulmonary infundibulum and proximal pulmonary artery. In Théveniau-Ruissy et al. (2008), genetic crosses using two transgene markers expressed in complementary subdomains of the embryonic OFT revealed that the myocardium at the base of the pulmonary trunk is reduced and malposed in the Tbx1 mutant heart, suggesting that the subpulmonary myocardial region is particularly Tbx1-dependent. Gene expression profiling of the AHF/SHF in Tbx1-null embryos showed that the genes regulating myocardial proliferation are downregulated (these include Isl1, Hod[unusual homeobox], and Nkx2.6), whereas genes for region-specific myocardial differentiation, such as Raldh2 (retinoic acid-synthesizing enzyme retinaldehyde dehydrogenase-2), Tbx5 and Gata4, are upregulated. Therefore, Tbx1 maintains the balance between proliferation and differentiation in the AHF/SHF by upregulating Isl1, Nkx2.6, and Hod, while downregulating Raldh2, Tbx5, and GATA4 (Liao et al. 2008). Human 22q11DS is most frequently associated with TF (74%) and is also often associated with pulmonary atresia and the major aortico-pulmonary collateral arteries (36%; Matsuoka et al. 1998). It seems likely that the TF seen in 22q11DS is caused by abnormal development and/or migration of the AHF/SHF. However, the morphological mechanisms controlled by Tbx1 are largely unknown.

ALTERED DEVELOPMENT OF ANTERIOR HEART FIELD/SECONDARY HEART FIELD MIGHT CAUSE TRANSPOSITION OF THE GREAT ARTERIES

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. DYNAMIC MOVEMENT OF HEART PROGENITOR CELLS DURING FORMATION OF THE PRIMITIVE HEART TUBE
  5. CONOTRUNCAL REGION IS ADDED TO THE PRIMITIVE HEART TUBE FROM BOTH THE PHARYNGEAL AND SPLANCHNIC MESODERM DURING LOOPING
  6. SIGNALING REGULATING THE FORMATION OF THE OUTFLOW TRACT FROM THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD
  7. ABNORMAL DEVELOPMENT OF THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD CAUSES CONOTRUNCAL HEART DEFECTS
  8. ANTERIOR HEART FIELD/SECONDARY HEART FIELD DEFECTS AND 22Q11.2 DELETION SYNDROME
  9. ALTERED DEVELOPMENT OF ANTERIOR HEART FIELD/SECONDARY HEART FIELD MIGHT CAUSE TRANSPOSITION OF THE GREAT ARTERIES
  10. INTERACTIONS BETWEEN THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD AND CARDIAC NEURAL CREST
  11. CONCLUSIONS
  12. ACKNOWLEDGMENTS
  13. REFERENCES

Transposition of the great arteries, in which the RV is connected to the ventrally malpositioned aorta, and the LV is connected to the dorsal pulmonary trunk, is a conotruncal heart defect (TGA in Fig. 3). The pathogenesis of TGA is disputed because of a lack of appropriate animal models. Maternal administration of retinoic acid induces TGA and TGA with DORV, in which a shortened OFT, hypoplastic OFT cushion tissues, decreased rotation of the distal OFT, and straight conotruncal septation are observed (Yasui et al. 1995 and 1999; Nakajima et al. 1996). Therefore, not only a rotated OFT but also well-developed spirally-oriented endocardial cushion ridges in the OFT are required for the establishment of spiral outflow channels and correct ventriculoarterial alignment. Retinoic acid is reported to suppress the expression of Tbx1 in the AHF/SHF (Roberts et al. 2005); therefore, it might be possible that maternally administered retinoic acid suppresses the expression of Tbx1, thereby affecting the proliferation/differentiation of cardiac progenitors in the AHF/SHF (Fig. 2). Pitx2 is a bicoid-related homeodomain transcription factor that regulates the late aspects of left–right axis formation as well as cardiac asymmetric morphology (Franco and Campione 2003). Pitx2 mull mice show DORV and TGA (Kitamura et al. 1999; Liu et al. 2003). Pitx2c, the left–right specific isoform, is expressed in the left lateral plate mesoderm, the left sides of the pharyngeal arch and splanchnic mesoderm, and the OFT myocardium (Kitamura et al. 1999; Liu et al. 2002). In Ai et al. (2006), inhibition of Pitx2c in AHF/SHF suppressed the proliferation of the second lineage of heart progenitors (but did not affect cardiac neural crest cells) and affected the elongation and rotation of the OFT, resulting in ventriculoarterial misalignment and, thereby, inducing DORV and TGA. (Ai et al. 2006). These observations strongly suggest that alterations in the signaling regulating the AHF/SHF and left–right asymmetry might cause TGA. However, the genetic and morphogenetic alterations that lead to TGA morphology are still uncertain (Bajolle et al. 2006).

INTERACTIONS BETWEEN THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD AND CARDIAC NEURAL CREST

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. DYNAMIC MOVEMENT OF HEART PROGENITOR CELLS DURING FORMATION OF THE PRIMITIVE HEART TUBE
  5. CONOTRUNCAL REGION IS ADDED TO THE PRIMITIVE HEART TUBE FROM BOTH THE PHARYNGEAL AND SPLANCHNIC MESODERM DURING LOOPING
  6. SIGNALING REGULATING THE FORMATION OF THE OUTFLOW TRACT FROM THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD
  7. ABNORMAL DEVELOPMENT OF THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD CAUSES CONOTRUNCAL HEART DEFECTS
  8. ANTERIOR HEART FIELD/SECONDARY HEART FIELD DEFECTS AND 22Q11.2 DELETION SYNDROME
  9. ALTERED DEVELOPMENT OF ANTERIOR HEART FIELD/SECONDARY HEART FIELD MIGHT CAUSE TRANSPOSITION OF THE GREAT ARTERIES
  10. INTERACTIONS BETWEEN THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD AND CARDIAC NEURAL CREST
  11. CONCLUSIONS
  12. ACKNOWLEDGMENTS
  13. REFERENCES

The importance of neural crest cells in cardiogenesis was documented more than 20 years ago (Kirby et al. 1983; Huston and Kirby 2007). Using neural crest-ablated chick embryos and quail-chick chimeras, Kirby et al. (1983) demonstrated that a subpopulation of cranial neural crest cells located between the otic placode and somite 3 (cardiac neural crest) migrate to the developing OFT through pharyngeal arches 3–6 and participate in septation of the OFT. Cardiac neural crest cells, which migrate into the OFT endocardial cushions, also contribute to the formation of the aortic and pulmonary valves. Therefore, surgical ablation of the premigratory cardiac neural crest cells results in predictable congenital heart defects involving the OFT and aortic arch arteries, such as PTA and interruption of the aortic arch. In Lo et al. (1997), in mice, transgenic expression of lacZ driven by the Cx43 promoter region showed that cardiac neural crest cells migrate to the OFT in a similar manner to that observed in avian embryos. The use of tissue-specific transgenes and Cre-Lox technology (promoter elements from the P0 (protein 0), Wnt1, Pax3 and PlexinA2), further confirms that cell-type specific expression of genetic programs acts to regulate neural crest function in cardiac development (Yamauchi et al. 1999; Jiang et al. 2000; Li et al. 2000; Brown et al. 2001). Interestingly P0, Wnt1 and Pax3 are not expressed in post-migratory neural crest cells within the heart, but PlexinA2 is expressed both in migrating and postmigratory cardiac neural crest cells (Brown et al. 2001).

In cardiac neural crest-ablated hearts, in addition to aorticopulmonary septum defects, the OFT is shortened, thereby causing decreased OFT rotation, decreased caudal displacement of the OFT, and incomplete wedging of the OFT, resulting in the dextroposed aorta seen in DORV and TF (Yelbuz et al. 2002). The shortened OFT seen in neural crest-ablated hearts is caused by decreased migration (but increased proliferation) of myocardial cells from the SHF during lengthening of the OFT (Waldo et al. 2005). Therefore, a reciprocal interaction between the two types of cells is apparent (Brown et al. 2001). Semaphorin3C/PlexinA2 signaling, in which Semaphorin3C is expressed in the OFT myocardium and PlexinA2 is expressed in the cardiac neural crest, might function to modulate the final positioning of neural crest cells in the OFT (Brown et al. 2001). In semaphorin3C deficient mice, cardiac neural crest cells fail to migrate into the OFT, thereby causing OFT septation defects. In Pax3/Splotch mutant mice, cardiac neural crest cells without Pax3 fail to invade the pharyngeal arches and OFT, affecting not only OFT septation but also genes expressed in the AHF/SHF (Chan et al. 2004; Bradshaw et al. 2009). These observations suggest that reciprocal interactions between the AHF/SHF and cardiac neural crest cells occur during cardiogenesis; however, this remains to be confirmed.

CONCLUSIONS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. DYNAMIC MOVEMENT OF HEART PROGENITOR CELLS DURING FORMATION OF THE PRIMITIVE HEART TUBE
  5. CONOTRUNCAL REGION IS ADDED TO THE PRIMITIVE HEART TUBE FROM BOTH THE PHARYNGEAL AND SPLANCHNIC MESODERM DURING LOOPING
  6. SIGNALING REGULATING THE FORMATION OF THE OUTFLOW TRACT FROM THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD
  7. ABNORMAL DEVELOPMENT OF THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD CAUSES CONOTRUNCAL HEART DEFECTS
  8. ANTERIOR HEART FIELD/SECONDARY HEART FIELD DEFECTS AND 22Q11.2 DELETION SYNDROME
  9. ALTERED DEVELOPMENT OF ANTERIOR HEART FIELD/SECONDARY HEART FIELD MIGHT CAUSE TRANSPOSITION OF THE GREAT ARTERIES
  10. INTERACTIONS BETWEEN THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD AND CARDIAC NEURAL CREST
  11. CONCLUSIONS
  12. ACKNOWLEDGMENTS
  13. REFERENCES

In conclusion, the second lineage of heart progenitor cells in the AHF/SHF, which is found in the pharyngeal and splanchnic mesoderm and is contiguous with the developing OFT, gives rise to the myocardium as well as the endocardium of the OFT. Experiments have shown that correct migration or proliferation of the AHF/SHF is important for remodeling of the OFT; therefore, abnormal development of the AHF/SHF causes conotruncal heart defects. Genes involved in AHF/SHF development, including Tbx1, Isl1 and Fgf8/10, have central roles in the genesis of the OFT. However, either the molecular or morphogenetic etiology that leads to particular heart defects is largely unknown. Further investigation focused on the AHF/SHF as well as the cardiac neural crest will disclose the etiology of conotruncal heart defects.

REFERENCES

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. DYNAMIC MOVEMENT OF HEART PROGENITOR CELLS DURING FORMATION OF THE PRIMITIVE HEART TUBE
  5. CONOTRUNCAL REGION IS ADDED TO THE PRIMITIVE HEART TUBE FROM BOTH THE PHARYNGEAL AND SPLANCHNIC MESODERM DURING LOOPING
  6. SIGNALING REGULATING THE FORMATION OF THE OUTFLOW TRACT FROM THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD
  7. ABNORMAL DEVELOPMENT OF THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD CAUSES CONOTRUNCAL HEART DEFECTS
  8. ANTERIOR HEART FIELD/SECONDARY HEART FIELD DEFECTS AND 22Q11.2 DELETION SYNDROME
  9. ALTERED DEVELOPMENT OF ANTERIOR HEART FIELD/SECONDARY HEART FIELD MIGHT CAUSE TRANSPOSITION OF THE GREAT ARTERIES
  10. INTERACTIONS BETWEEN THE ANTERIOR HEART FIELD/SECONDARY HEART FIELD AND CARDIAC NEURAL CREST
  11. CONCLUSIONS
  12. ACKNOWLEDGMENTS
  13. REFERENCES
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