Glial cell line-derived neurotrophic factor rescues target-deprived sympathetic spinal cord neurons but requires transforming growth factor-beta as cofactor in vivo

Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor for several populations of CNS and peripheral neurons. Synthesis an d storage of GDNF by the neuron-like adrenal medullary cells suggest roles in adrenal functions and/or in the maintenance of spinal cord neurons that innervate the adrenal medulla. We show that unilateral adrenomedullectomy c auses degeneration of all sympathetic preganglionic neurons within the inte rmediolateral column (IML) of spinal cord segments T7-T10 that project to t he adrenal medulla. In situ hybridization revealed that IML neurons express the glycosylphosphatidylinositol-linked alpha receptor 1 and c-Ret recepto rs, which are essential for GDNF signaling. IML neurons also display immuno reactivity for transforming growth factor-beta (TGF-beta) receptor II. Admi nistration of GDNF (recombinant human, 1 mu g) in Gelfoam implanted into th e medullectomized adrenal gland rescued all Fluoro-Gold-labeled preganglion ic neurons projecting to the adrenal medulla after four weeks. Cytochrome c applied as a control protein was not effective. The protective effect of G DNF was prevented by co-administration to the Gelfoam of neutralizing antib odies recognizing all three TGF-beta isoforms but not GDNF. This suggests t hat the presence of endogenous TGF-beta was essential for permitting a neur otrophic effect of GDNF. Our data indicate that GDNF has a capacity to prot ect a population of autonomic spinal cord neurons from target-deprived cell death. Furthermore, our results demonstrate for the first time that the pr eviously reported requirement of TGF-beta for permitting trophic actions of GDNF in vitro (Krieglstein et al., 1998) also applies to the in vivo situa tion.