ABSTRACT
The receptor tyrosine kinase RET has recently been shown to serve as a functional receptor for the glialderived neurotrophic factor (GDNF). RET binds to GDNF in conjunction with an accessory receptor chain, GDNFR-α. These three proteins are expressed in a number of sites in the developing peripheral and central nervous systems, as well as in the developing excretory system. Studies of mice with targeted mutations in the genes encoding RET and GDNF have established that both genes are required for the normal development of the metanephric (adult) kidney, and for the enteric nervous system and parts of the sympathetic nervous system. The development of the metanephric kidney is unique among glandular organs because the epithelial components derive from mesenchyme as well as epithelium. The epithelial component, the ureteric bud, induces the metanephric mesenchyme to condense into epithelial vesicles and differentiate into the nephrons of the mature kidney. Simultaneously, the metanephric mesenchyme induces growth and arborization of the ureteric bud which eventually forms the collecting system of the kidney. RET is expressed in the ureteric bud of the developing kidney, while GDNF expression is localized to the metanephric mesenchyme, and together they mediate the inductive effect of the metanephric mesenchyme on the ureteric bud. The peripheral nervous system is formed by the migration and differentiation of neural crest cells, many of which express RET, while GDNF is expressed in a complementary pattern in the surrounding mesenchyme. GDNF/RET signaling is of particular importance for the survival and proliferation of a specific subpopulation of neural crest, the sympathoenteric lineage, which form the parts of the enteric and sympathetic nervous systems.
