TRANSGENIC EXPRESSION OF THE ENDOTHELIN-B RECEPTOR PREVENTS CONGENITAL INTESTINAL AGANGLIONOSIS IN A RAT MODEL OF HIRSCHSPRUNG-DISEASE

The spotting lethal rat, a naturally occurring rodent model of Hirschs prung disease, carries a deletion in the endothelin-B receptor (EDNRB) gene that abrogates expression of functional EDNRB receptors. Rats ho mozygous for this mutation (sl) exhibit coat color spotting and congen ital intestinal aganglionosis. These deficits result from failure of t he neural crest-derived epidermal melanoblasts and enteric nervous sys tem (ENS) precursors to completely colonize the skin and intestine, re spectively. We demonstrate that during normal rat development, the EDN RB mRNA expression pattern is consistent with expression by ENS precur sors throughout gut colonization. We used the human dopamine-beta-hydr oxylase (DPH) promoter to direct transgenic expression of EDNRB to col onizing ENS precursors in the sl/sl rat. The D beta H-EDNRB transgene compensates for deficient endogenous EDNRB in these rats and prevents the intestinal defect. The transgene has no effect on coat color spott ing, indicating the critical time for EDNRB expression in enteric nerv ous system development begins after separation of the melanocyte linea ge from the ENS lineage and their common precursor. The transgene dosa ge affects both the incidence and severity of the congenital intestina l defect, suggesting dosage-dependent events downstream of EDNRB activ ation in ENS development.