or treatment for waardenburg's syndrome. hirschsprung's disease also implicated in defects related to neural crest cell development and migration is hirschsprung's disease (hd or hscr), characterized by a lack of innervation in regions of the intestine. this lack of innervation can lead to further physiological abnormalities like an enlarged colon (megacolon), obstruction of the bowels, or even slowed growth. in healthy development, neural crest cells migrate into the gut and form the enteric ganglia. genes playing a role in the healthy migration of these neural crest cells to the gut include ret, gdnf, gfrα, edn3, and ednrb. ret, a receptor tyrosine kinase (rtk), forms a complex with gdnf and gfrα. edn3 and ednrb are then implicated in the same signaling network. when this signaling is disrupted in mice, aganglionosis, or the lack of these enteric ganglia occurs. fetal alcohol spectrum disorder prenatal alcohol exposure (pae) is among the most common causes of developmental defects. depending on the extent of the exposure and the severity of the resulting abnormalities, patients are diagnosed within a continuum of disorders broadly labeled fetal alcohol spectrum disorder (fasd). severe fasd can impair neural crest migration, as evidenced by characteristic craniofacial abnormalities including short palpebral fissures, an elongated upper lip, and a smoothened philtrum. however, due to the promiscuous nature of ethanol binding, the mechanisms by which these abnormalities arise is still unclear. cell culture explants of neural crest cells as well as in vivo developing zebrafish embryos exposed to ethanol show a decreased number of migratory cells and decreased distances travelled by migrating neural crest cells. the mechanisms behind these changes are not well understood, but evidence suggests pae can increase apoptosis due to increased cytosolic calcium levels caused by ip3-mediated release of calcium from intracellular stores. it has also been proposed that the decreased viability of ethanol-exposed neural crest cells is caused by increased oxidative stress. despite these, and other advances much remains to be discovered about how ethanol affects neural crest development. for example, it appears that ethanol differentially affects certain neural crest cells over others; that is, while craniofacial abnormalities are common in pae, neural crest-derived pigment cells appear to be minimally affected. digeorge syndrome digeorge syndrome is associated with deletions or translocations of a small segment in the human chromosome 22. this deletion may disrupt rostral neural crest cell migration or development. some defects observed are linked to the pharyngeal pouch system, which receives contribution from rostral migratory crest cells. the symptoms of digeorge syndrome include congenital heart defects, facial defects, and some neurological and learning disabilities. patients with 22q11 deletions have also been reported to have higher incidence of schizophrenia and bipolar disorder. treacher collins syndrome treacher collins syndrome (tcs) results from the compromised development of the first and second pharyngeal arches during the early embryonic stage, which ultimately leads to mid and lower face abnormalities. tcs is caused by the missense mutation of the tcof1 gene, which causes neural crest cells to undergo apoptosis during embryogenesis. although mutations of the tcof1 gene are among the best characterized in their role in tcs, mutations in polr1c and polr1d genes have also been linked to the pathogenesis of tcs. cell lineages neural crest cells originating from different positions along the anterior-posterior axis develop into various tissues. these regions of neural crest can be divided into four main functional domains, which include the cranial neural crest, trunk neural crest, vagal and sacral neural crest, and cardiac neural crest. cranial neural crest main article: cranial neural crest cranial neural crest migrates dorsolaterally to form the craniofacial mesenchyme that differentiates into various cranial ganglia and craniofacial cartilages and bones. these cells enter the pharyngeal pouches and arches where they contribute to the thymus, bones of the middle ear and jaw and the odontoblasts of the tooth primordia. trunk neural crest main article: trunk neural crest trunk neural crest gives rise two populations of cells. one group of cells fated to become melanocytes migrates dorsolaterally into the ectoderm towards the ventral midline. a second group of cells migrates ventrolaterally through the anterior portion of each sclerotome. the cells that stay in the sclerotome form the dorsal root ganglia, whereas those that continue more ventrally form the sympathetic ganglia, adrenal medulla, and the nerves surrounding the aorta. vagal and sacral neural crest the vagal and sacral neural crest cells develop into the ganglia of the enteric nervous system and the parasympathetic ganglia. cardiac neural crest main article: cardiac neural crest cardiac neural crest develops into melanocytes, cartilage, connective tissue and neurons of some pharyngeal arches. also, this domain gives rise to regions of the heart such as the musculo-connective tissue of the large arteries, and part of the septum, which divides the pulmonary circulation from the aorta. the semilunar valves of the heart are associated with neural crest cells according to new research. evolution several structures that distinguish the vertebrates from other chordates are formed from the derivatives of neural crest cells. in their "new head" theory, gans and northcut argue that the presence of neural crest was the basis for vertebrate specific features, such as sensory ganglia and cranial skeleton. furthermore, the appearance of these features was pivotal in vertebrate evolution because it enabled a predatory lifestyle. however, considering the neural crest a vertebrate innovation does not mean that it arose de novo. instead, new structures often arise through modification of existing developmental regulatory programs. for example, regulatory programs may be changed by the co-option of new upstream regulators or by the employment of new downstream gene targets, thus placing existing networks in a novel context. this idea is supported by in situ hybridization data that shows the conservation of the neural plate border specifiers in protochordates, which suggest that part of the neural crest precursor network was present in a common ancestor to the chordates. in some non-vertebrate chordates such as tunicates a lineage of cells (melanocytes) has been identified, which are similar to neural crest cells in vertebrates. this implies that a rudimentary neural crest existed in a common ancestor of vertebrates and tunicates. neural crest derivatives ectomesenchyme (also known as mesectoderm): odontoblasts, dental papillae, the chondrocranium (nasal capsule, meckel's cartilage, scleral ossicles, quadrate, articular, hyoid and columella), tracheal and laryngeal cartilage, the dermatocranium (membranous bones), dorsal fins and the turtle plastron (lower vertebrates), pericytes and smooth muscle of branchial arteries and veins, tendons of ocular and masticatory muscles, connective tissue of head and neck glands (pituitary, salivary, lachrymal, thymus, thyroid) dermis and adipose tissue of calvaria, ventral neck and face endocrine cells: chromaffin cells of the adrenal medulla, glomus cells type i/ii. peripheral nervous system: sensory neurons and glia of the dorsal root ganglia, cephalic ganglia (vii and in part, v, ix, and x), rohon-beard cells, some merkel cells in the whisker, satellite glial cells of all autonomic and sensory ganglia, schwann cells of all peripheral nerves. enteric cells: enterochromaffin cells. melanocytes and iris muscle and pigment cells, and even associated with some tumors (such as melanotic neuroectodermal tumor of infancy).