GDNF DEFICIT IN HIRSCHSPRUNGS-DISEASE

Background/Purpose: In 1996, the glial cell line-derived neurotrophic factor (GDNF) was identified as one of the ligands of the RET transmem brane receptor. In the same year, GDNF mutations were found in associa tion with RET protooncogene mutations in Hirschsprung patients. Mutati ons in GDNF per se are thought neither necessary nor sufficient to cau se Hirschsprung's disease (HD). To date, our study group has identifie d GDNF mutations only in 2 of 98 cases of intestinal dysganglionosis. The aim of our study was to investigate a possible expression deficit of GDNF in the enteric nervous system of Hirschsprung patients not mut ated for the GDNF gene. Methods: We used rabbit polyclonal antibodies raised against a peptide corresponding to amino acids 186-205 mapping within the carboxy-terminal domain of human GDNF. GDNF expression was studied immunohistochemically in surgical specimens from 30 HD cases ( 27 classic forms and 3 ultralong forms) and from 10 age-matched contro ls. Serial sections from the same full-thickness specimens were invest igated with the following histochemical and immunohistochemical techni ques: acetylcholinesterase, lactate dehydrogenase, succinic dehydrogen ase, alpha-naphthylesterase, glial fibrillary acid protein, S-100 prot ein, and neuron-specific enolase. Results: A high level of GDNF expres sion was found in normal intestine and in Hirschsprung ganglionic segm ent. Satellite elements of myenteric ganglia presented a strong immuno reactivity to GDNF. Conversely, the aganglionic segment showed choline rgic hyperinnervation and hypertrophic trunks of nerve fibers in the m uscular interstitium with complete absence of GDNF expression. The sma ll ganglia of the hypoganglionic segment showed a reduced GDNF immunor eactivity. Conclusions: GDNF, a distantly related member of the transf orming growth factor-beta superfamily, is a potent neurotrophic and su rvival factor for neurons and enteric ganglion cells. Mutations of the GDNF gene or GDNF expression deficit interrupt the faithful GDNF sign aling via Ret, contributing to HD pathogenesis. Copyright (C) 1998 by W.B. Saunders Company.