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(Circulation Research. 1995;77:211-215.)
© 1995 American Heart Association, Inc.

Articles

Neural Crest and Cardiovascular Patterning

Margaret L. Kirby, Karen L. Waldo

From the Heart Development Group, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta.

Correspondence to Dr Margaret L. Kirby, Heart Development Group, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, GA 30912-2000. E-mail mkirby@mail.mcg.edu.

Key Words: neural crest • heart development • aortic archpatterning • myocardial function • cardiac dysmorphogenesis

	Introduction

Top Introduction A Quick Review of... Cardiac Neural Crest and... Neural Crest and Myocardial... Other Animal Models Conclusions References

 
Ablation of the cardiac neural crest has provided a powerful model of cardiovascular dysmorphogenesis because removal or manipulation of neural crest cells can be done before migration in sites distant from central cardiovascular development in chick embryos. Because the heart begins to function so early in its own morphogenetic history, the cardiovascular system is exquisitely sensitive to the embryonic environment, and virtually any manipulation of the embryo has cardiovascular consequences. Thus, although neural crest manipulation is not devoid of experimental artifact, it has resulted in significant advances in our understanding of certain of the factors involved in normal heart development in a way that direct manipulation of heart development does not. We have now identified two major roles for the neural crest in cardiovascular patterning. These are (1) participation in the patterning of the pharyngeal arches and their derivatives, including the aortic arch arteries, which will become the great arteries of the thorax, and (2) migration of a discrete population of neural crest cells into the cardiac outflow tract and participation in formation of the outflow septum. With the advent of genetically based animal models of cardiovascular dysmorphogenesis, some of which are neural crest related, it becomes important to understand what we know definitively from the ablation model along with the questions that remain. This review will focus on the roles of the neural crest in cardiovascular patterning as seen in the ablation model. An important part of the emerging neural crest–ablation phenotype is an early change in the functional competency of the developing myocardium. We believe that the neural crest–ablation phenotype provides a prototype for comparison with newer models of neural crest–related cardiovascular dysmorphogenesis and that the changes in myocardial functional development provide a means of understanding the early mortality associated with neural crest–type cardiac dysmorphogenesis.

	A Quick Review of Heart and Pharyngeal Development

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The four-chambered heart develops from a single (initially and very briefly) straight tube composed of three layers: an inner endocardium and outer myocardium separated by a thick extracellular matrix called cardiac jelly (Fig 1).¹ The growing tube loops, with the convexity of the loop demarcating a functional inflow from an outflow portion of the looped tube (Fig 1). This original convexity forms the two ventricles by expansion and septation, and as the ventricular septum forms, the inflow and outflow must be redefined.¹ Initially, all of the inflow is through the atrioventricular canal connecting a common atrium to the presumptive left ventricle; all of the outflow is from the presumptive right ventricle into the aortic sac via the conotruncus. Several septa are formed simultaneously, making a rearrangement of inflow and outflow critical. The atrioventricular canal is divided into left and right channels, the nascent right and left ventricles are separated by the ventricular septum, the conotruncus is converted into aortic vestibule and semilunar valve continuous with the left ventricle, and the pulmonary infundibulum and semilunar valve originating from the right ventricle.

View larger version (30K): [in this window] [in a new window]   Figure 1. A, Major events in development of the heart from a single straight tube. Early looping is probably a function of the myocardium. Convergence of the outflow and inflow tracts occurs during late looping and is critical for normal wedging. Wedging produces alignment of the three components that complete outflow septation. B, Prototypical cardiac malformations after cardiac neural crest ablation, demonstrating the clear separation of alignment and outflow septation. CT indicates conotruncus; S, aortic sac; A, aorta; V, ventricle; P, pulmonary trunk; RA, right atrium; LA, left atrium; RV, right ventricle; LV, left ventricle; and PTA, persistent truncus arteriosus.

The initial impetus for cardiac looping appears to be programmed into the myocardium and is inaccessible to extraneous factors; however, during the later stages of looping, the configuration of the loop can be altered by experimental manipulation. This second stage of looping involves convergence of the inflow and outflow tracts, which is needed for alignment to occur properly. After the outflow and inflow tracts have converged, a new period of adjustment is needed to bring the outflow tract into correct orientation with the appropriate ventricles. This process, called "wedging," brings the aortic side of the conotruncus to nestle between the mitral and tricuspid valves. Outflow septation occurs concurrently with the wedging process so that the outflow septum, having reached the base of the conus, is in the correct position or alignment for final convergence with the ventricular septum and atrioventricular endocardial cushion tissue. If wedging does not occur, or occurs improperly, these three septal components do not meet, resulting in a ventricular septal defect. The early events in looping and convergence of outflow and inflow tracts are critical for normal wedging. Abnormalities of looping and convergence can result in both inflow (ie, double-inlet left ventricle) and outflow (ie, double-outlet right ventricle) malalignments, whereas abnormal wedging only affects the position of the outflow tract.

Blood flows from the outflow tract to the aortic sac and then to the dorsal aorta via a series of five paired aortic arch arteries that develop sequentially in the pharyngeal arches.^{2 3} The aortic sac is remodeled into the base of the aorta and pulmonary trunk by formation of the aortopulmonary septum, which appears in the dorsal wall of the aortic sac between arch arteries 4 and 6. The aortopulmonary septum is continued into the truncal and conal regions of the cardiac tube as the truncal septum dividing the aortic and pulmonary semilunar valves; then most proximally, the conal septum divides the aortic vestibule from the pulmonary infundibulum.¹ Failure of the outflow septum to form results in persistent truncus arteriosus, a condition in which there is a single outflow vessel with a single valve.

The aortic arch arteries are originally bilaterally symmetrical and develop in series, with the first two regressing into capillary beds in their respective pharyngeal arches. The caudal three aortic arch arteries, located in pharyngeal arches 3, 4, and 6 persist and after extensive remodeling become the brachiocephalic and common carotid arteries, the arch of the aorta, and the ductus arteriosus (Fig 2). Aortic arch 5 exists very briefly and is not associated with an independent pharyngeal arch.

View larger version (0K): [in this window] [in a new window]   Figure 2. Illustration of aortic arch artery development and the persisting arterial derivatives. a, Development on the right side of the five vessels, each within its own pharyngeal arch. Arch 1 has regressed into a capillary bed, and arch 2 is beginning to break down into a capillary bed. Arch arteries 3, 4, and 6 persist as major vessels, as shown in panels b and c. b and c, Persisting derivatives of arch arteries 3, 4, and 6 in the chick (b) and in the mouse or human (c). Ao indicates aorta; P, pulmonary trunk; RPA and LPA, right and left pulmonary arteries, respectively; RD and LD, right and left ductus arteriosus, respectively; RBC and LBC, right and left brachiocephalic arteries, respectively; RSC and LSC, right and left subclavian arteries, respectively; and RCC and LCC, right and left common carotid arteries, respectively.

	Cardiac Neural Crest and the Ablation Phenotype

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Neural crest cells originating in the cranial region have the potential to differentiate into mesenchymal or neural cell lineages.⁴ Neural crest cells migrate to the pharyngeal arches, where they are important for structural development of all of the arch derivatives. Pharyngeal arches 1 and 2 contribute to the lower face/upper neck and ear.⁴ Neural crest cells originating from the hindbrain region at the level of rhombomeres 6, 7, and 8 (midotic placode to somite 3) migrate via the circumpharyngeal region to the caudal 3 pharyngeal arches.⁵ A subpopulation of the neural crest–derived cells in these pharyngeal arches continues its migration into the outflow tract of the developing heart tube and forms both the aortopulmonary and conotruncal portions of the outflow septation complex.⁶ Thus, these cells have two spatiotemporally separate roles in cardiovascular development: they are involved in development of the aortic arch arteries, becoming the smooth muscle cells of the tunica media of the persisting arteries, and they participate in formation of the outflow septum.⁶

The catalogue of cardiac malformations after ablation of the premigratory cardiac neural crest includes persistent truncus arteriosus, double-outlet right ventricle, tetralogy of Fallot, double-inlet left ventricle, tricuspid atresia, straddling tricuspid valve, and the absence of a varying combination of aortic arch arteries derived from pharyngeal arches 3, 4 (interrupted aortic arch), and 6 (absent ductus arteriosus), which persist under normal circumstances (Fig 3).⁷ Atrioventricular canal and transposition of the great vessels are seen so rarely after ablation of the cardiac neural crest that they are not classified in the chick as neural crest–related defects. Several noncardiac defects also occur from disrupted development of the caudal pharyngeal arches, including thymus, thyroid, and parathyroid hypoplasia or agenesis (Fig 3).⁸ The intracardiac defects can be divided into two major categories: absence of outflow septation (ie, persistent truncus arteriosus) and malalignment defects typified by double-outlet right ventricle, where a robust outflow septum forms but is malaligned with regard to the ventricular septum (Fig 1).

View larger version (21K): [in this window] [in a new window]   Figure 3. Flow chart to illustrate the functional and structural consequences of cardiac neural crest ablation. DORV indicates double-outlet right ventricle; PTA, persistent truncus arteriosis; and Ao, aorta.

After neural crest ablation, alignment abnormalities of the phenotypically mature heart can be predicted early in development from the configuration of the looped tube before alignment.⁹ An abnormally wide separation between the outflow and inflow tracts can be observed well before the process of outflow septation and wedging begins. The separation appears to be due to ventricular dilation, which in turn is necessary to maintain normal cardiac output.¹⁰ In addition to neural crest ablation, the configuration of the looped tube can be affected by the degree of embryonic cervical flexure,¹¹ direct manipulation of the outflow tract,¹² and teratogens such as retinoic acid.¹³

After neural crest ablation, a decrease in myocardial contractility accompanies ventricular dilation (Fig 3). The ventricular dilation is thought to be necessary to maintain a normal cardiac output from the functionally impaired ventricle. If the cardiac output is not maintained, the embryo is likely to die.⁹ If the ventricle dilates to maintain cardiac output, the embryo is more likely to live but at the expense of normal convergence of the inflow/outflow tracts, leading to alignment defects such as double-outlet right ventricle and occasionally double-inlet left ventricle.⁹ Because looping occurs during the period when the pharyngeal arches are forming and being populated by neural crest cells (Fig 4) and removal of neural crest results in alignment abnormalities, it seemed reasonable to suggest that pharyngeal patterning might play a role in normal cardiac looping and alignment. In support of this idea, many experiments have shown looping abnormalities after clamping the aortic arch arteries (reviewed by Rychter¹⁴ ). However, two recent experiments have shown that mispatterning of the pharyngeal and aortic arches does not result in abnormal heart development. Ablation of a single pharyngeal arch field before formation of a functional arch artery results in the same variety of aortic arch malformations seen with neural crest ablation but no change in ventricular function, as is seen after neural crest ablation,¹⁵ and no alignment defects. At the molecular level, alteration of the Hox proteins, expressed by neural crest migrating to pharyngeal arches 3, 4, and 6, results in predictable abnormalities in aortic arch patterning, but these appear to be unrelated to alignment defects in the heart (M.L. Kirby, P. Hunt, and P. Thorogood, unpublished data, 1995). This is further supported by the hoxa-3 null mutation, in which the glandular derivatives of arches 3 and 4 do not form, indicating pharyngeal arch mispatterning, but no heart defect results.¹⁶ Thus, patterning of the pharyngeal arches is dependent on the neural crest and is apparently related to expression of appropriate sets of Hox genes. Furthermore, inappropriate patterning of the pharyngeal arches leads to defects of the aortic arch derivatives and mispatterning of the branches of the outflow vessels of the heart; however, inappropriate patterning of the pharyngeal arches does not appear to affect cardiac development.

View larger version (11K): [in this window] [in a new window]   Figure 4. A time line illustrating the events in cardiac neural crest development as they relate to the events in heart development in the chick. Although the timing is somewhat different in mammals, the sequence of events and relations are the same. CNC indicates cardiac neural crest; AP, aortopulmonary; and CT, conotruncus.

	Neural Crest and Myocardial Function

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Another aspect of the neural crest–ablation phenotype, which has received little recognition as yet, is abnormal myocardial function. Functional characteristics of the myocardium during earliest cardiac function are predictive of the severity of the cardiovascular defects that will develop as well as the odds of survival for the embryo.⁹ Hemodynamic abnormalities occur well before the period when normal septation occurs.^{10 11} These embryos compensate for decreased contractility by ventricular dilation, enabling them to maintain an adequate cardiac output for survival.⁹ It is thought that these functional compensations in very early cardiac development may play an etiologic role in the subsequent development of structural heart defects. At older ages, when septation would normally be complete, these embryos have reduced ejection fraction, and the myocardium shows poor contractility.¹⁷ Poor cardiac function is further indicated by reduced embryo weight and edema.¹⁸

The gross signs of cardiac dysfunction observed in the intact heart can be explained, in large part, by impairment of myocardial contractility, which includes defects in the steps linking excitation of the membrane to the rise in intracellular Ca²⁺, which activates contraction, and in the contractile apparatus itself. Hearts destined to develop persistent truncus arteriosis have reduced L-type Ca²⁺ current as early as embryonic day 3.¹⁹ The reduction in Ca²⁺ current is associated with a reduction in the number of functional L-type Ca²⁺ channels.¹⁹ These changes occur in the neural crest–ablation model of cardiac dysmorphogenesis, but it is not known if they occur generally in conjunction with cardiac defects. Furthermore, since mispatterning of the pharyngeal arches does not result in functional deficits in the developing myocardium, what is the trigger for these functional changes?

	Other Animal Models

Top Introduction A Quick Review of... Cardiac Neural Crest and... Neural Crest and Myocardial... Other Animal Models Conclusions References

 
Three mouse models have recently expanded our opportunity to investigate both the molecular and cellular basis of neural crest participation in the pathogenesis of heart defects. The Splotch mutant mouse phenotype is the closest to the ablation model of any that have so far appeared. Splotch mutant alleles have long been known to disrupt neural crest development, resulting in defects of neural crest derivatives including melanocytes and dorsal root ganglia.²⁰ Recently, it was demonstrated that Sp^2H homozygotes also develop persistent truncus arteriosus²¹ with accompanying ventricular septal defect (S. Conway, A. Copp, unpublished data, 1995). Approximately 50% of Splotch embryos die at 13.5 days of gestation. The Splotch mutation disrupts the Pax3 gene,²² which encodes a DNA-binding transcription factor. We do not know if myocardial function is abnormal in Splotch mutants, but it is a potential explanation for the high early lethality of this mutation.

Neurofibromatosis type 1 is an autosomal-dominant disease with phenotypic manifestations resulting from abnormalities of neural crest–derived tissues.²³ The neurofibromatosis type-1 gene (NF-1) is a tumor suppressor gene with extensive homology with two negative regulators of Ras, IRA1 and IRA2. NF-1 shares homology with the domain of mammalian GAP that encodes the GTPase-activation function. The GAP domain negatively regulates Ras by catalyzing the conversion of the active GTP-bound form of Ras (active) to the inactive GDP-bound form. Targeted disruption of NF-1 causes in utero death between 13.5 and 14.5 days of gestation. The death may be due to the presence of heart defects resembling double-outlet right ventricle.²³ Interestingly, a consensus sequence in the 3' untranslated region of the NF-1 gene is homologous to a consensus binding site for Pax3, which can activate transcription.²⁴ Thus, expression of Pax3 may be important for expression of NF-1 in neural crest cells.

Compound null mutations of retinoic acid receptor genes result in many of the same phenotypic characteristics associated with neural crest ablation, including persistent truncus arteriosus, dextroposition of the ascending aorta or double-outlet right ventricle, and anomalous development of aortic arch arteries and pharyngeal arch derivatives.²⁵ The persistent truncus usually arises from the right ventricle, indicating that wedging has not occurred, but occasionally overrides the ventricular septum. Inflow anomalies are present but rare. Retinoic acid is known to affect Hox gene expression in the rhombencephalon, potentially leading to defective patterning of the pharyngeal arches,²⁶ and since retinoic acid receptors occur on cardiomyocytes, it probably also has a direct effect on myocardial development. A point of difference between the ablation model and animals with retinoic acid receptor mutations is that the myocardial wall is thinner in the mutation, perhaps from this direct effect. Although the myocardium is functionally altered in the ablation model, it is not grossly or histologically abnormal.

	Conclusions

Top Introduction A Quick Review of... Cardiac Neural Crest and... Neural Crest and Myocardial... Other Animal Models Conclusions References

 
The neural crest is important in two aspects of cardiovascular patterning: outflow septation and aortic arch derivatives. Ablation of the cardiac neural crest results in absence of the outflow septum (persisting truncus arteriosus) and mispatterning of the great arteries (ie, interrupted aortic arch). At the same time, neural crest ablation affects two separate events in cardiac morphogenesis: alignment and outflow septation. The alignment defects are induced before the neural crest is in the heart and can be dissociated from patterning in the pharyngeal arches, leading to the conclusion that there must be an alternate explanation for their occurrence. The alignment defects appear to be related to abnormal functional characteristics of the nascent ventricular myocardium during the looping period, causing ventricular dilation associated with an inability of the inflow and outflow tracts to converge properly.

The neural crest–ablation model provides a standard that can be used to evaluate new models of cardiac dysmorphogenesis in an attempt to understand the function of individual genes and events in heart development. Although appropriate testing has not been done in genetically based animal models of cardiac neural crest dysfunction, it can be speculated that the high mortality associated with these defects may be due to myocardial dysfunction.

Finally, it is not known what initiates the myocardial dysfunction associated with neural crest ablation. One possibility is the existence of a factor that acts directly on the early myocardium during looping and causes changes in the myocardial cell developmental program. A similar change in the myocardial developmental program may also be induced by retinoic acid and several of the other known cardiac teratogens.

An important part of final patterning or phenotype in the cardiovascular system is the result of a continuing discussion between myocardial and neural crest–derived cells or their products. This conversation leads to a final phenotype that is either normal, abnormal but viable, or abnormal and lethal. The ability of the myocardium to adapt is probably compromised in the presence of continuing abnormal demands that are at least in part self-generated. Thus the system becomes progressively fragile in responding to functional changes. It is extremely important in characterizing new models of cardiovascular dysmorphogenesis to have a correct analysis of the final phenotype of central cardiovascular structures in order to begin sorting out the events leading to this final phenotype. Only with the information in place regarding the continuing interactions of structure and function can we understand the ultimate phenotype. At this point, it will be possible to understand the role of specific genes in the initial events in dysmorphogenesis and the factors important in cardiovascular patterning. This is an especially exciting time in heart development because we are on the verge of understanding the molecular mechanisms that underpin neural crest–related heart development.

	Acknowledgments

 
My sincere thanks to my colleague Dr Tony Creazzo for continuing discussions regarding the neural crest–ablation model and this manuscript, to Dr Adriana Gittenberger-de Groot for continuing discussions about heart development and introducing me to the concept of wedging, to Dr Dale Bockman for help with this manuscript, and to all my collaborators here and elsewhere for their goodwill and participation.

Received November 30, 1994; accepted March 28, 1995.

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