Cardiac neural crest: the holy grail of cardiac abnormalities?

See article by Conway et al. [1] (pages 314 –328) in pharyngeal arch 6) is referred to as the cardiac neural crest. this issue. This part is called cardiac neural crest because it provides mesenchymal cells to the heart and the great arteries. In this issue of Cardiovascular Research the group of Moreover, the cardiac neural crest not only contributes Conway presents convincing data showing that the phenocells to the heart but also to the thymus, thyroid and 2H type of the Splotch Sp mouse is the result of a decrease parathyroid glands. The neural crest-derived mesenchymal in the absolute numbers of pre-migratory cardiac neural cells are often referred to as ectomesenchyme to discrimicrest cells rather than to a malfunctioning of the cardiac nate them from ‘‘normal’’ mesenchymal cells that are neural crest cells. These observations touch upon the derived from mesoderm and implicitly suggesting they are important question of whether the quality, i.e. neural crest intrinsically different [2–7]. origin or merely the quantity of the mesenchyme is Cardiac neural crest cells have fascinated many cardiac important for proper outflow tract (OFT) septation [1]. developmental biologists. This fascination takes origin During early development neural folds are formed along from the idea that the ectomesenchymal cells upon their the anteroposterior-axis in the ectoderm. Upon fusion the detachment from the ectoderm and their epithelial to folds give rise to the neural tube. During the process of mesenchymal transition would maintain a special characneural tube formation, cells detach at the border of the ter. With respect to the heart this issue has focused onto the neural and epidermal ectoderm, i.e. at the dorsal aspect of conduction system and outflow tract septation. The presthe forming neural tube. These cells are referred to as ence of neural-like proteins, like neurofilament, in the neural crest cells. Neural crest cells migrate along defined conduction system [8,9] has led to a continuing debate as pathways throughout the body. Upon arrival at their to whether the conduction system would have a neurodestination, they differentiate into various cell types, ectodermal origin. However, the heart has developed an among which melanocytes, peripheral neurons and their electrocardiogram (ECG) [10] indicating the presence of supporting cells, and skeletal elements. The neural crest sinuatrial and atrioventricular nodal function well before cells are formed along the entire cranio–caudal axis of the the arrival of neural crest cells in the heart [6,11]. This body and can be divided into two major populations the debate has led to lineage analysis studies by Mikawa and cranial and truncal neural crest cells. The cranial neural coworkers [12]. Evidence so far is in favour of a carcrest extends from the diencephalon up to somite pair 5, diogenic origin of the conduction system. A role of the and the truncal neural crest from somite pair 6 to the neural crest in the maturation of the conduction system has caudal end of the neural tube. The truncal neural crest is been put forward, based on the spatial association of neural involved in sympathetic innervation of the heart, whereas crest cells and the cardiac conduction system in the the cranial neural crest is associated with parasympathetic developing heart [13]. However, genetically modified mice innervation of the heart. The part of the cranial neural crest in which the neural crest is impaired, have not been that extends from the mid-otic placode (or cleft between reported to have cardiac conduction system abnormalities, pharyngeal arch 2 and 3) to the level of somite pair 3 (or 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, *Corresponding author. University of Amsterdam, Department of intracellular calcium transients, and uneven production of Anatomy and Embryology, Meibergdreef 15, 1105 AZ Amsterdam, The cardiac jelly. This time point coincides with the arrival of Netherlands. Tel.: 131-20-566-5378; fax: 131-20-697-6177. E-mail address: [email protected] (M.J.B. van den Hoff). the neural crest cells in the dorsal aspect of the pharyngeal