Hirschsprung's disease is a neuronal dysplasia of the hindgut, charact
erised by a loss of neurones, which affects about 1 in 5000 live birth
s.(1) Genetic factors have been implicated in the aetiology of this di
sease in about 20% of cases and a dominant pattern of inheritance has
been revealed in several families.(2 3) The pathogenesis of the agangl
ionosis is often attributed to a failure of migration of neural crest
cells, although this has not been proven. Recently, mutations in a dev
elopmentally regulated receptor tyrosine kinase gene, ret, and mutatio
ns in the endothelin receptor-B gene (ENDR-B) have both been linked to
familial Hirschsprung's disease in humans.(4-6) Moreover, certain mut
ant mouse strains-namely piebald lethal and lethal spotted-exhibit str
iking similarities to the human condition. The mutation which gives ri
se to piebald lethal has now been found to be in the ENDR-B gene,(7) a
nd the mutation associated with lethal spotted occurs in the gene for
endothelin-3 (ET-3), a ligand for ENDR-B.(8) Two transgenic mouse line
s have been developed which also reflect the human disease: ret-k(-),
which has a loss of function mutation of the ret gene,(9) and ENDR-B n
ull.(10) In addition, the introduction of a Lac-Z reporter gene into n
eural crest cells of aganglionic mice has made it possible to study di
rectly the fate of enteric neuroblasts which are affected by ''Hirschs
prung's-like'' mutations.(11) Here, we review the possible roles of RE
T and endothelin in the normal development of the enteric nervous syst
em, and the significance of their mutated forms in the pathogenesis of
familial aganglionosis. This review focuses on recent advances in our
understanding of the genetic basis of the lesions which have been imp
licated in congenital forms of Hirschsprung's disease. Disruption of t
hese genes in the mouse, either by transgenic ''knockout'' approaches
or in mutant mouse lines, offers the prospect of greater understanding
of both the cellular and developmental bases of the human disease.