BACKGROUND/PURPOSE: In 1996, the glial cell line-derived neurotrophic factor 
(GDNF) was identified as one of the ligands of the RET transmembrane receptor. 
In the same year, GDNF mutations were found in association with RET 
protooncogene mutations in Hirschsprung patients. Mutations in GDNF per se are 
thought neither necessary nor sufficient to cause Hirschsprung's disease (HD). 
To date, our study group has identified 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 mutated 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 controls. Serial sections from the same full-thickness specimens 
were investigated with the following histochemical and immunohistochemical 
techniques: acetylcholinesterase, lactate dehydrogenase, succinic dehydrogenase, 
alpha-naphthyl-esterase, glial fibrillary acid protein, S-100 protein, and 
neuron-specific enolase.
RESULTS: A high level of GDNF expression was found in normal intestine and in 
Hirschsprung ganglionic segment. Satellite elements of myenteric ganglia 
presented a strong immunoreactivity to GDNF. Conversely, the aganglionic segment 
showed cholinergic hyperinnervation and hypertrophic trunks of nerve fibers in 
the muscular interstitium with complete absence of GDNF expression. The small 
ganglia of the hypoganglionic segment showed a reduced GDNF immunoreactivity.
CONCLUSIONS: GDNF, a distantly related member of the transforming growth 
factor-beta superfamily, is a potent neurotrophic and survival factor for 
neurons and enteric ganglion cells. Mutations of the GDNF gene or GDNF 
expression deficit interrupt the faithful GDNF signaling via Ret, contributing 
to HD pathogenesis.