The enteric nervous system.

T HE enteric nervous system is a collection of neu-rons in the gastrointestinal tract 1 that constitutes the " brain of the gut " and can function independently of the central nervous system. 2 This system controls the motility, 3,4 exocrine and endocrine secretions, 5 and microcirculation 6 of the gastrointestinal tract; it is also involved in regulating immune and inflammatory processes. 7 In the past decade, major advances in the understanding of the enteric nervous system have led to a greater appreciation of its importance in clinical medicine. In this review we highlight some of these advances. The enteric nervous system is primarily derived from cells of the vagal segment of the neural crest that migrate to the cranial portion of the gut and subsequently move caudally to populate the entire gastrointestinal tract. 8 The ganglia of the hindgut receive an additional contribution from the sacral segment of the neural crest. Several receptors with tyrosine kinase activity are important in the migration and development of neuroblasts in the gut. One of these receptors, Ret, is involved in the development of enteric ganglia derived from vagal-neural-crest cells. 9 Targeted disruption of the RET gene in mice results in the lack of enteric gan-glia and in renal agenesis. 9 Mutations in the RET gene are associated with megacolon in humans. 10,11 Kit, another receptor with tyrosine kinase activity, is involved in the development of the interstitial cells of Cajal. 12 These are nonneural cells that serve as pacemakers and are responsible for the spontaneous, rhythmic, electrical excitatory activity of gastrointestinal smooth muscle that is referred to as slow waves. These cells are also important in modulating communication between nerve and muscle. Mice with mutations in the KIT gene lack interstitial cells and have changes in skin pigment and abnormal intestinal motility. 13 Endothelin-3 and endothelin-B receptors also have a role in the migration and development of the enteric nervous system, as well as in the development of mel-anocytes from the neural crest. 14,15 Both targeted disruption of the endothelin-3 gene in mice and naturally occurring mutations of this gene (in lethal spotting mice) cause aganglionic megacolon and coat-color spotting. 14 A similar phenotype results from targeted disruption of the gene for the endothelin-B receptor in mice and natural mutations of the receptor gene in piebald lethal mice. 15 Mutations in this gene have been reported in patients with Hirschsprung's disease. The …