EDNRB/EDN3 and Hirschsprung disease Type II

The study of vertebrate pigmentary anomalies has greatly improved our under standing of melanocyte biology. One such disorder, Waardenburg syndrome (WS ), is a mendelian trait characterized by hypopigmentation and sensorineural deafness. It is commonly subdivided into four types (WS1-4), defined by th e presence or absence of additional symptoms. WS type 4 (WS4), or Shah-Waar denburg syndrome, is also known as Hirschsprung disease Type II (HSCR II) a nd is characterized by an absence of epidermal melanocytes and enteric gang lia, Mutations in the genes encoding the endothelin type-B receptor (EDNRB) and its physiological ligand endothelin 3 (EDN3) are now known to account for the majority of HSCR II patients. Null mutations in the mouse genes Edn rb and Edn3 have identified a keg role for this pathway in the normal devel opment of melanocytes and other neural crest-derived lineages. The pleiotro pic effects of genes in this pathway, on melanocyte and enteric neuron deve lopment, have been clarified by the embryologic identification of their com mon neural crest (NC) ancestry. EDNRB and EDN3 are transiently expressed in crest-derived melanoblast and neuroblast precursors, and in the surroundin g mesenchymal cells, respectively, The influence of EDNRB-mediated signalin g on the emigration, migration, proliferation, and differentiation of melan ocyte and enteric neuron precursors, in vivo and in vitro has recently been the subject of great scrutiny. A major emergent theme is that EDN3-induced signaling prevents the premature differentiation of melanocyte and enteric nervous system precursors and is essential between 10 and 12.5 days post-c oitum, We review the present understanding of pigment cell development in t he context of EDNRB/EDN3 - a receptor-mediated pathway with pleiotropic eff ects.