COMPLEMENTARY AND OVERLAPPING EXPRESSION OF GLIAL-CELL LINE-DERIVED NEUROTROPHIC FACTOR (GDNF), C-RET PROTOONCOGENE, AND GDNF RECEPTOR-ALPHA INDICATES MULTIPLE MECHANISMS OF TROPHIC ACTIONS IN THE ADULT-RAT CNS

Glial cell line-derived neurotrophic factor (GDNF), the most potent tr ophic factor yet described for both dopaminergic neurons of the substa ntia nigra and spinal motorneurons, has recently been shown to signal through a multireceptor complex composed of a novel glycosylphosphatid ylinositol-anchored GDNF receptor-alpha (GDNFR-alpha) and the receptor tyrosine kinase product of the c-ret proto-oncogene (RET). Despite it s importance, the individual expression patterns and the relationships between domains of expression of the different components of this tro phic system are not understood. We show here by in situ hybridization that GDNF mRNA is expressed in the normal adult rat brain in several t argets of substantia nigra neurons, including striatum, nucleus accumb ens, thalamic nuclei, olfactory tubercle, hippocampus, cerebellum, and cingulate cortex as well as in the internal granular cell layer of th e olfactory bulb. Within the basal ganglia we observe a pronounced seg regation of regions expressing GDNF from those expressing GDNF recepto rs, suggesting that within these structures GDNF is functioning in its anticipated role as a target-derived trophic factor. In addition, the expression of GDNF and both GDNF receptors within the cerebellum, hip pocampus, and olfactory bulb may indicate a paracrine mode of action. Importantly, we also see expression of RET mRNA in cellular population s within the cerebellum and the glomerular layer of the olfactory bulb , as well as in the subthalamic nucleus, which lack GDNFR-alpha expres sion, indicating that RET functions either independently of GDNFR-alph a or with GDNFR-alpha presented in trans. Conversely, GDNFR-alpha is w idely expressed in many regions in which RET expression is absent, sug gesting that GDNFR-alpha may associate with additional signaling recep tors. Finally, RET and GDNFR-alpha show distinct patterns of regulated expression in the brain after kainic acid stimulation and in the scia tic nerve after nerve transection. Taken together these findings indic ate that GDNF, RET, and GDNFR-alpha utilize multiple mechanisms to com prise physiologically relevant trophic circuits for different neuronal populations.