Introduction to Endothelin-3/Endothelin-B Receptor and SOX10 Signaling Pathways

Abstract

Abstract Hirschsprung disease [congenital absence of the distal enteric nervous system (ENS)] and Waardenburg syndrome (pigment abnormalities and sensorineural deafness) result from abnormal embryonic development of neural crest (NC)-derived cells. These developmental abnormalities occur together in humans (Shah–Waardenburg syndrome, also known as Waardenburg syndrome type IV) and in several species of animals. The Shah–Waardenburg syndrome is caused by mutations in the genes that encode the endothelin-B receptor (EDNRB), one of its ligands (endothelin-3, EDN3), and the Sex-determining Region Y (SRY)-related high mobility group (HMG)-box gene 10 (SOX10) (see Chapter 54). EDNRB and SOX10 are both critical components of a signaling cascade that controls the development of melanocytes and the ENS. Despite the similarities of the skin and enteric phenotypes observed in EDN3, EDNRB, and SOX10 mutant animals and humans, the interaction of these pathways in vivo is not yet fully de7ned, although some recent data suggest that SOX10 may regulate EDNRB expression in a tissueand developmental-stage–speci7c manner (Zhu et al., 2004; Hakami et al., 2006; Yokoyama et al., 2006).