THE RET-GLIAL CELL-DERIVED NEUROTROPHIC FACTOR (GDNF) PATHWAY STIMULATES MIGRATION AND CHEMOATTRACTION OF EPITHELIAL-CELLS

Embryonic development requires cell migration in response to positiona l cues. Yet, how groups of cells recognize and translate positional in formation into morphogenetic movement remains poorly understood. In th e developing kidney, the ureteric bud epithelium grows from the nephri c duct towards a group of posterior intermediate mesodermal cells, the metanephric mesenchyme, and induces the formation of the adult kidney . The secreted protein GDNF and its receptor RET are required for uret eric bud outgrowth and subsequent branching. However, it is unclear wh ether the GDNF-RET pathway regulates cell migration, proliferation, su rvival, or chemotaxis. In this report, we have used the MDCK renal epi thelial cell line to show that activation of the RET pathway results i n increased cell motility, dissociation of cell adhesion, and the migr ation towards a localized source of GDNF. Cellular responses to RET ac tivation include the formation of lamellipodia, filopodia. and reorgan ization of the actin cytoskeleton. These data demonstrate that GDNF is a chemoattractant for RET-expressing epithelial cells and thus accoun t for the developmental defects observed in RET and GDNF mutant mice. Furthermore, the RET-transfected MDCK cells described in this report a re a promising model for delineating RET signaling pathways in the ren al epithelial cell lineage.