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Cardiovascular Research 2000 47(2):212-216; doi:10.1016/S0008-6363(00)00127-9
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Copyright © 2000, European Society of Cardiology

Cardiac neural crest: the holy grail of cardiac abnormalities?

Maurice J.B. van den Hoff* and Antoon F.M. Moorman

Experimental and Molecular Cardiology Group, Cardiovascular Research Institute Amsterdam, Academic Medical Center, Amsterdam, The Netherlands

* Corresponding author. University of Amsterdam, Department of Anatomy and Embryology, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. Tel.: +31-20-566-5378; fax: +31-20-697-6177 m.j.vandenhoff{at}amc.uva.nl

Received 11 May 2000; accepted 15 May 2000

See article by Conway et al. [1] (pages 314–328) in this issue.

In this issue of Cardiovascular Research the group of Conway presents convincing data showing that the phenotype of the Splotch Sp2H mouse is the result of a decrease in the absolute numbers of pre-migratory cardiac neural crest cells rather than to a malfunctioning of the cardiac neural crest cells. These observations touch upon the important question of whether the quality, i.e. neural crest origin or merely the quantity of the mesenchyme is important for proper outflow tract (OFT) septation [1].

During early development neural folds are formed along the anteroposterior-axis in the ectoderm. Upon fusion the folds give rise to the neural tube. During the process of neural tube formation, cells detach at the border of the neural and epidermal ectoderm, i.e. at the dorsal aspect of the forming neural tube. These cells are referred to as neural crest cells. Neural crest cells migrate along defined pathways throughout the body. Upon arrival at their destination, they differentiate into various cell types, among which melanocytes, peripheral neurons and their supporting cells, and skeletal elements. The neural crest cells are formed along the entire cranio–caudal axis of the body and can be divided into two major populations the cranial and truncal neural crest cells. The cranial neural crest extends from the diencephalon up to somite pair 5, and the truncal neural crest from somite pair 6 to the caudal end of the neural tube. The truncal neural crest is involved in sympathetic innervation of the heart, whereas the cranial neural crest is associated with parasympathetic innervation of the heart. The part of the cranial neural crest that extends from the mid-otic placode (or cleft between pharyngeal arch 2 and 3) to the level of somite pair 3 (or pharyngeal arch 6) is referred to as the cardiac neural crest. This part is called cardiac neural crest because it provides mesenchymal cells to the heart and the great arteries. Moreover, the cardiac neural crest not only contributes cells to the heart but also to the thymus, thyroid and parathyroid glands. The neural crest-derived mesenchymal cells are often referred to as ectomesenchyme to discriminate them from "normal" mesenchymal cells that are derived from mesoderm and implicitly suggesting they are intrinsically different [2–7].

Cardiac neural crest cells have fascinated many cardiac developmental biologists. This fascination takes origin from the idea that the ectomesenchymal cells upon their detachment from the ectoderm and their epithelial to mesenchymal transition would maintain a special character. With respect to the heart this issue has focused onto the conduction system and outflow tract septation. The presence of neural-like proteins, like neurofilament, in the conduction system [8,9] has led to a continuing debate as to whether the conduction system would have a neuro-ectodermal origin. However, the heart has developed an electrocardiogram (ECG) [10] indicating the presence of sinuatrial and atrioventricular nodal function well before the arrival of neural crest cells in the heart [6,11]. This debate has led to lineage analysis studies by Mikawa and coworkers [12]. Evidence so far is in favour of a cardiogenic origin of the conduction system. A role of the neural crest in the maturation of the conduction system has been put forward, based on the spatial association of neural crest cells and the cardiac conduction system in the developing heart [13]. However, genetically modified mice in which the neural crest is impaired, have not been reported to have cardiac conduction system abnormalities, as yet [7,14]. On the other hand, pre-migratory cardiac neural crest ablation in chickens results already after 24 h in abnormal cardiomyocyte proliferation and disarray, intracellular calcium transients, and uneven production of cardiac jelly. This time point coincides with the arrival of the neural crest cells in the dorsal aspect of the pharyngeal arches [15]. The abnormal cardiac function is already observed prior to the arrival of the cardiac neural crest in the heart, and was found to be due to a decrease in the number of functional L-type Ca2+ channels in the sarcolemma of the cardiomyocytes [16], rather than to an impaired cardiac conduction system. Interestingly, these early effects on the heart in the absence of cardiac neural crest are suggested to be due to a prolonged release of growth factors by the pharyngeal endoderm, that are normally involved in the induction of cardiac mesoderm [15].

Concerning the contribution of the cardiac neural crest to the OFT evidence is much more solid. Unique molecular markers that allow the unambiguous identification and tracking of neural crest and neural crest-derived cells during development are lacking. Hence, indirect methods have to be used among which are quail-chicken chimeras and viral labelling of pre-migratory neural crest cells. Pre-migratory cardiac neural crest cells of the chicken have surgically been removed and replaced by the quail cardiac neural crest (i.e. quail-chicken chimeras). The quail-derived cells can be identified based on their different nuclear histology from chicken cell nuclei and/or by immunostaining of a quail nuclear antigen using the QCPN monoclonal antibody [2,17–19]. Secondly, the pre-migratory cardiac neural crest cells have been labelled using replication deficient viruses [13,20–22]. These experiments showed that cardiac neural crest cells migrate from the neural tube into the pharyngeal arches 3, 4 and 6 and from there to the heart. At the arterial pole of the heart the cardiac neural crest cells form the aortic-pulmonary septum that projects into the aortic sac from the basis between aortic arch arteries 4 and 6. In the formed heart the neural crest cells of the aortico-pulmonary septum form the facing walls of the aorta and pulmonary trunk, whereas more distally (cranially) a tunica media entirely derived from neural crest surrounds the aorta and pulmonary trunk. Proximal of the aortico-pulmonary septum the neural crest cells form two finger-like projections, referred to as prongs, of condensed ectomesenchyme into the distal OFT ridges that become dispersed in the proximal OFT ridges.

Based on the principle of guilty by association, the cardiac neural crest cells present in the OFT ridges have been suggested to be involved in fusion of the ridges and subsequent myocardialization of the proximal OFT ridges, becoming the muscular outlet septum in the formed heart [23,24]. Though direct evidence is lacking the following observations are very suggestive of a role for cardiac neural crest in OFT septation. In quail-chicken chimeras quail cells have been found to line up below the endocardium prior to fusion of the endocardial ridges [18]. In immunohistochemical analyses on mouse and rat, a monoclonal antibody directed against alpha-smooth muscle actin (SMA) identifies a sub-population of mesenchymal cells in the outflow tract ridges, presumably being neural crest derived cells. These SMA-positive mesenchymal cells are aligned longitudinally prior to fusion of the ridge but form a whorl-like structure at the site of fusion of the ridges, suggesting an important role in initiating and/or enforcing fusion of the ridges [23]. Furthermore, these SMA-positive mesenchymal cells were found to line up with the myocardializing cardiomyocytes, that migrate into the cardiac cushions, like they are pulling the cardiomyocytes into the flanking mesenchyme [25]. A regulatory role of cardiac neural crest in myocardialization is also suggested by in vitro culture experiments. These experiments showed (i) that only outflow tracts explanted after arrival of the neural crest cells are able to show spontaneous myocardialization in vitro, (ii) that conditioned media prepared of the aortic sac were found to contain factors that are able to induce myocardialization of early outflow tract explants, i.e. explanted before arrival of the cardiac neural crest in the outflow tact [24].

Cardiac neural crest ablation experiments demonstrated that upon removal of the pre-migratory cardiac neural crest cardiovascular abnormalities are induced. The pre-migratory neural crest is ablated by removal of the dorsal aspects of the neural folds using vibrating needles, tungsten needles, or laser. Entire removal of the cardiac neural crest showed in almost all cases a persistent truncus arteriosus (PTA). However, the chicken neural crest ablation phenotype also includes abnormal patterning of the great arteries that are derived from the aortic arches, absence or hypoplastic thymus, thyroid and parathyroids. As expected, removal of only the cardiac neural crest does not effect the innervation of the heart and does not lead to craniofacial abnormalities. Interestingly, partial ablation of the cardiac neural crest results in a milder cardiac phenotype, like double outlet right ventricle, dextraposed aorta, tetralogy of Fallot, and/or ventricle septum defect, whereas the other phenotypic alterations are hardly different from complete cardiac neural crest ablation [17,26–29]. Based on these ablation studies it was concluded that PTA only occurred when the numbers of neural crest cells were reduced below a critical level that is no longer compatible with proper formation of the aortico-pulmonary septum [5,30]. Thus, the ablation experiments are in agreement with the conclusion of Conway and coworkers [1] suggesting that the quantity rather than the quality of neural crest cells is important in OFT septation.

Furthermore, cardiac malformations associated with partial ablation of the cardiac neural crest, show normal formation of the aortico-pulmonary septum and as a result an aorta and a pulmonary trunk. However, the aorta and pulmonary trunk are malaligned with respect to the ventricles. One might argue that the neural crest-derived cells are not only crucial in the regulation of septation but also in the alignment of the great arteries with respect to the ventricles. On the other hand one might argue that the malalignment is due to an indirect effect of neural crest ablation. Several observations support the latter conclusion: (i) Ablation of the crest cranially of the cardiac neural crest results in a dextraposed aorta in 23% of the embryos with cardiovascular abnormalities but in none of the embryos a PTA was found [28]. (ii) In line with these observations, unilateral ablation of the pre-cardiac neural crest results in double outlet right ventricle in 15% of the analyzed embryos [27]. (iii) Even without directly manipulating neural crest cells malalignment of the great-arteries is frequently observed. Preventing cervical flexion by placing suture material in the neural groove [31] or a straight hair in the neural tube [32] results in 83% and 23% malalignment of the great arteries, respectively. (iv) Inducing haemodynamic changes, by clipping one of the vitelline veins, prior to arrival of the neural crest cells in the heart OFT results in 90% of the embryos with cardiac malformations in abnormalities ranging from double outlet right ventricle to ventricular septum defects, but never in a PTA [33,34]. (v) Placing a ligature around the base of the OFT prior or after arrival of the neural crest in the OFT resulted in all embryos in a double outlet right ventricle, and even in two-thirds of the embryos when the ligature was removed after 24 h [35]. (vi) From personal observations we know that alignment abnormalities are also frequently seen after simple touching of the OFT (unpublished). Thus, because ablating the cranial neural crest, preventing cervical flexure, altering haemodynamics, and manipulating the heart during early development frequently induces malpositioning of the great arteries with respect to the ventricles, it seems that alignment abnormalities are not due to malfunctioning of the cardiac neural crest, but rather the result of experimental manipulation.

Finally, early ablation studies frequently reported inflow tract abnormalities (20% of successfully ablated embryos), whereas in other studies the frequency of these abnormalities is much lower. Inflow tract abnormalities are not to be expected because in the chicken-quail chimera studies quail cardiac neural crest cells were never observed in the venous pole of the heart [2,36–38]. Therefore, the difference in frequency of inflow tract abnormalities is most probably due to improvement of the techniques used to ablate the dorsal aspect of the neural fold without damaging the underlying cell layers. In this respect, it is interesting that cells from the ventral aspect of the neural tube have recently been reported to invade the heart at the venous pole [13,39]. It would be interesting to see whether prevention of invasion of this population of neural cells into the venous pole of the heart would result in inflow tract abnormalities.

In many genetically modified mice, OFT malformations are reported that are suggested, without direct evidence, to be the result of malfunctioning of the neural crest [6,7,14]. So far, the best phenocopy of the chicken cardiac neural crest ablations is the Splotch mutant mouse, and in particular the Sp2H variant. In Splotch Sp2H mice a 32 bp deletion in the Pax3 gene results in a truncated protein that is lacking a homeobox, such that the Pax3 transcription factor is biologically inactive [40]. Homozygous Splotch Sp2H mice have all died by embryonic day 16 and show persistent truncus arteriosus, aortic arch abnormalities, defects of the thymus, thyroid and parathyroid as well as pigmentation, neural tube closure and limb musculature defects. The group of Conway has extensively studied the involvement of neural crest in the cardiovascular phenotype of the Splotch Sp2H mouse [41–43]. Using molecular markers they previously showed that the migrating cardiac neural crest cells were deficient in the Splotch Sp2H mouse. In this issue of Cardiovascular Research [1] this analysis was further extended and they show that the limited numbers of cardiac neural crest cells observed in Splotch Sp2H mice do behave normally with respect to a number of parameters such as proliferation, apoptosis and migration, but that the numbers of initially formed neural crest cells during neural fold closure is greatly reduced. The reduced number of pre-migratory cardiac neural crest cells is reflected in a reduced and altered spatial expression of the Wnt-1 gene in the forming neural tube. Based on these observations the authors suggest that already the number of neuro-ectodermal cells determined to become neural crest cells, i.e. stem cells, seems to be reduced. Nevertheless, it is now clear that in the Splotch Sp2H mice the cardiovascular phenotype is not due to the quality but due to the quantity of cardiac neural crest cells. What still remains to be figured out is how this apparently critical amount of cardiac neural crest cells ending up in the OFT is involved at the molecular and cellular level in the regulation of the fusion of the outflow tract ridges and their subsequent myocardialization.

Also in humans, many syndromes have been suggested to be the result of improper development, expansion and/or migration of the cardiac neural crest, but this is mostly based on the phenotype of these syndromes that includes elements of the chicken cardiac neural crest ablation phenotype [7,30]. The best phenocopy in humans is the DiGeorge syndrome. The DiGeorge syndrome includes hypocalcemia, defective thymic-dependent cellular immunity, abnormalities of the face, ears and palate, interrupted aortic arch and persistent truncus arteriosus or some degree of overriding aorta [44]. The abnormalities of the face, ears and palate are not observed in cardiac neural crest ablated chicken embryo, but are present when the cranial neural crest that migrates through pharyngeal arches 1 and 2, is ablated [28]. The complexity of the regulation of the contribution of neural crest cells in the different aberrant tissues in DiGeorge syndrome is further underscored by the identification of several genes in the region of the microdeletion of chromosome 22q11 associated with DiGeorge-syndrome. Moreover, neither of these genes alone, when functionally disrupted in mice, seems to be able to fully explain the observed phenotype [45,46].

Taken together, the role of cardiac neural crest seems to be rather modest during development. The only evidence, thus far, is that the amount of mesenchyme derived of the cardiac neural crest is critical rather than its origin. Thus far, no evidence has been put forward with respect to a role of cardiac neural crest in the development of the cardiac conduction system or a specific role in the septational process. Therefore, we doubt whether the cardiac neural crest should be considered as The Holy Grail of cardiac abnormalities.


   Acknowledgements
 
We thank Dr JM Ruijter for critically reading of the manuscript. Dr MJB van den Hoff is financially supported by the The Netherlands Heart Foundation grant M96.002.


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