Soluble and bound forms of GFRalpha1 elicit different GDNF-independent neurite growth responses in primary sensory neurons.

We have investigated the role of glial cell-line derived neurotrophic factor (GDNF) and the effect of soluble or immobilized localization of its GDNF family receptor alpha1 (GFRalpha1) on neurite growth in cultured embryonic Bax(-/-) dorsal root ganglion neurons, which survive in the absence of trophic support. Whereas GDNF alone has a moderate effect on neurite growth, soluble and immobilized GFRalpha1 elicit opposing and GDNF-independent effects on neurite growth by a phospholipase C (PLC) gamma-dependent mechanism. Thus, GFRalpha1 elicits nerve growth responses independent of GDNF. However, GDNF in the presence of soluble or immobilized GFRalpha1 reverse the GDNF-independent GFRalpha1 modulation of neurite growth. The different outcome of soluble and bound GFRalpha1 combined with our previous immunohistochemical data showing GFRalpha1-protein in Schwann cells but not axons suggest terminal Schwann cells as a source of locally administered target-derived GFRalpha1 and place this receptor in the path of axonal growth and guidance. Thus, target-derived GFRalpha1 play opposing roles when presented alone and with GDNF and, therefore, can function as a nerve growth cue that both can promote and prevent growth in the developing peripheral nervous system.