Neurotrophic factors are secreted molecules that are responsible for many functions in the development, differentiation and survival of mainly neural but also other tissues. The glial cell line-derived neurotrophic factor, GDNF, is a potent survival factor for the midbrain dopaminergic neurons that was found to signal through a tyrosine kinase receptor, Ret. This receptor complex includes other, glycosylphosphoinositol-linked proteins, termed GFRa s, that were found to form a family of homologous molecules involved in the signaling of GDNF and its relatives.

GDNF and Ret are crucial for the development of the kidney and the enteric nervous system of the digestive tract. The expression of GDNF mRNAs was found in the muscularis mucosae of the developing human colon whereas the receptors were expressed in the ganglia of the entire digestive tract. In the kidney, GDNF was found to be responsible for the budding of the ureter from the Wolffian duct.

The gene encoding GDNF was analyzed for mutations in diseases that are closely linked to the biology of GDNF or its receptors. No disease causing mutations were found in the samples from the patients suffering from Hirschsprung’s disease (aganglionic megacolon), renal aplasia or Parkinson’s disease.

Another important group of neurotrophic factors are called neurotrophins. They all bind to p75 neurotrophin receptor (p75NTR) and to the different members of the receptor tyrosine kinases. p75NTR is expressed in the kidney and nervous system, as well as in non-neuronal cells in some other tissues. The p75NTR gene was analyzed in the patients of a lethal disorder, Meckel syndrome with a developmental defect in the renal, limb and brain morphogenesis. One heterozygous polymorphism was found and shown not to be the disease mutation. The p75NTR gene was then mapped outside the Meckel locus.