GDNF elicits distinct immediate-early gene responses in cultured cortical and mesencephalic neurons

Glial cell line-derived neurotrophic factor (GDNF) has been recognized as a survival-promoting molecule for several neuronal populations in the central nervous system (CNS), including midbrain dopaminergic neurons and cortical neurons. Whereas it is well established that GDNF affects dopaminergic cell survival through a receptor complex composed of the tyrosine kinase, Ret, and the glycosylphosphatidylinositol (GPI)-anchored protein, GFRalpha-1, c-Ret is basically undetectable in cortical neurons. In the present study, we have compared GDNF signaling in cortical and mesencephalic neurons by using GDNF-induced expression of the immediate-early genes, c-fos and mgif, as a readout. We found that stimulation of embryonic day (E)17 cortical cultures for 3 hr with GDNF at concentrations ranging from 10 to 80 ng/ml did not result in detectable c-fos expression. In contrast, c-fos expression occurred in E14 mesencephalic cultures exposed to both low and high GDNF concentrations. Vice versa, cortical neurons responded to high GDNF concentrations (80 ng/ml) with an increase in mRNA encoding mGIF, while a similar mGIF response was absent in mesencephalic cultures. Cleavage of GFRalpha receptor subunits from their GPI anchors by phosphatidylinositol-specific phospholipase C (PIPLC) abolished GDNF-induced c-fos expression in mesencephalic cultures, but did not interfere with the effects of GDNF on cortical mgif expression. Together, these findings point to distinct differences in the GDNF recognition and/or signal transduction machinery of cortical and mesencephalic neurons.