GDNF FAMILY SIGNALLING IN EXOCRINE TISSUES: DISTINCT ROLES FOR GDNF AND NEURTURIN IN PARASYMPATHETIC NEURON DEVELOPMENT Jari Rossi and Matti S. Airaksinen Program in Molecular Neurobiology Institute of Biotechnology, Viikki Biocenter 00014 University of Helsinki, Finland 1. INTRODUCTION Glial cell line-derived neurotrophic factor (GDNF) and related neurotrophic factors neurturin (NRTN), artemin (ARTN) and persephin (PSPN) form a subgroup in the trans- forming growth factor-β superfamily. They signal by binding to a receptor complex consisting of a ligand-binding GPI-anchored GDNF family receptor α (GFRα1 to GFRα4) and the trans-membrane tyrosine kinase Ret (for review see (1-3)). A schematic view of the GDNF family signaling is shown in Figure 1. Ret GFL GFRα TK Lipid raft -P Src Src P- -P GDNF Ret NRTN PSPN ARTN GFRα3 GFRα4 GFRα2 GFRα1 The autonomic or vegetative nervous system is subdivided into three distinct systems, the sympathetic, parasympathetic and enteric nervous system, which regulate the internal Figure 1. (Left) GDNF-family ligands and receptor interactions. All GDNF family ligands (GFLs) activate Ret tyrosine kinase via GPI-anchored GFRα receptors. Solid arrows indicate the preferred functional ligand-receptor interactions, whereas “cross-talk” interactions represented by dotted arrows may not be physiologically significant in vivo. (Right) A model of GDNF family signaling based on (22). The GFL first binds a GFRα receptor that is concentrated in lipid rafts. The GFL/GFRα-complex is able to bind and recruit Ret into the raft, thereby activating the tyrosine kinase (TK) domain of Ret and various downstream signaling complexes, including Src-type kinases. An alternative model also exists where GFL binds to the pre- associated GFRα/Ret complex (23)