Role of the endothelin system in normal development

Three known mammalian endothelins, ET-1, ET-2, and ET-3, are each encoded by separate genes and expressed in a variety of vascular and nonvascular tissues. Two subtypes of endothelin receptors have been identified and termed endothelin-A and endothelin-B receptors (ET-A and ET-B). In the first part of this study, the ET-A gene was disrupted in mouse embryonic stem cells to generate mice deficient in ET-A.In the second part of this study, we investigated a targeted disruption of the mouse ET-B gene that results in aganglionic megacolon associated with coat color spotting, resembling a hereditary syndrome of mice, humans and other mammalian species (Waardenburg syndrome).In the third part of this study, we demonstrated that a targeted disruption of the mouse endothelin-3 ligand (ET-3) gene produces a similar recessive phenotype of megacolon and coat color spotting.Two types of endothelin converting enzymes (ECE-1 and ECE-2) have been recently identified. In the last part of this study, we investigated the expression of ECE-1 in human tissues using immunohistochemistry and in situ hybridization, and compared it to those of ET-1 and big ET-1. (Abstract shortened by UMI.