The RET-glial cell-derived neurotrophic factor (GDNF) pathway stimulates migration and chemoattraction of epithelial cells.
Embryonic development requires cell migration in response to positional cues. Yet, how groups of cells recognize and translate positional information into morphogenetic movement remains poorly understood. In the developing kidney, the ureteric bud epithelium grows from the nephric 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 ureteric bud outgrowth and subsequent branching. However, it is unclear whether the GDNF-RET pathway regulates cell migration, proliferation, survival, or chemotaxis. In this report, we have used the MDCK renal epithelial cell line to show that activation of the RET pathway results in increased cell motility, dissociation of cell adhesion, and the migration towards a localized source of GDNF. Cellular responses to RET activation include the formation of lamellipodia, filopodia, and reorganization of the actin cytoskeleton. These data demonstrate that GDNF is a chemoattractant for RET-expressing epithelial cells and thus account for the developmental defects observed in RET and GDNF mutant mice. Furthermore, the RET-transfected MDCK cells described in this report are a promising model for delineating RET signaling pathways in the renal epithelial cell lineage.
Tang
M J
MJ
Department of Pathology and Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
Worley
D
D
Sanicola
M
M
Dressler
G R
GR
D000818:Animals; D002452:Cell Count / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002630:Chemotactic Factors / Q000494:pharmacology; D002633:Chemotaxis / Q000502:physiology*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004285:Dogs; D029721:Drosophila Proteins; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009924:Organ Culture Techniques; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection / Q000235:genetics; D014513:Ureter / Q000254:growth & development
D002630:Chemotactic Factors; D003598:Cytoskeletal Proteins; D029721:Drosophila Proteins; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila