| Abstract: | MRC Brain Development Programme,Department of Developmental Neurobiology,UMDS Guy's Hospital,London SE1 9RT, UK S HALL Hirschsprung's disease is a neuronal dysplasia of the hindgut,characterised by a loss of neurones, which affects about 1in 5000 livebirths.1 Genetic factors have been implicated in theaetiology of this disease in about 20% of cases and a dominant patternof inheritance has been revealed in several families. The pathogenesis of the aganglionosis is often attributed to a failureof migration of neural crest cells, although this has not been proven.
Recently, mutations in a developmentally regulated receptor tyrosinekinase gene, ret, and mutations in the endothelinreceptor-B gene (ENDR-B) have both been linked to familialHirschsprung's disease in humans.4-6 Moreover, certainmutant mouse strains—namely piebald lethal and lethal spotted—exhibitstriking similarities to the human condition. The mutation which givesrise to piebald lethal has now been found to be in the ENDR-Bgene,7 and the mutation associated with lethal spottedoccurs in the gene for endothelin-3 (ET-3), a ligand forENDR-B.8
Two transgenic mouse lines have been developed which also reflect thehuman disease: ret-k , which has aloss of function mutation of the retgene,9 and ENDR-B null.10 In addition, theintroduction of a Lac-Z reporter gene into neural crest cells ofaganglionic mice has made it possible to study directly the fate ofenteric neuroblasts which are affected by "Hirschsprung's-like"mutations.11 Here, we review the possible roles of RET andendothelin in the normal development of the enteric nervous system, andthe significance of their mutated forms in the pathogenesis of familialaganglionosis.
This review focuses on recent advances in our understanding of thegenetic basis of the lesions which have been implicated in congenitalforms of Hirschsprung's disease. Disruption of these genes in themouse, either by transgenic "knockout" approaches or in mutantmouse lines, offers the prospect of greater understanding of both thecellular and developmental bases of the human disease.
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