TGF beta trophic factors differentially modulate motor axon outgrowth and protection from excitotoxicity

Transforming growth factor (TGF) beta-like trophic factors have been shown to be protective in acute neuronal injury paradigms. In the current study, we analyzed and compared members of this growing family, including glial ce ll line-derived neurotrophic factor (GDNF), neurturin, nodal, persephin, an d TGF beta 1, for protection against chronic glutamate toxicity. In paralle l, we developed a organotypic spinal cord culture system to study the abili ty of these factors to promote motor axon outgrowth across white matter. Us ing these systems, we were able to differentiate the neuroprotective effect of the TGF beta-like factors from their motor axon outgrowth-promoting act ivity. GDNF, neurturin, persephin, nodal, and TGF beta 1 all protected agai nst excitotoxic motor neuron degeneration. Low amounts of GDNF (1 ng/ml) an d high concentrations of neurturin induced vigorous motor axon outgrowth. I n contrast, nodal, persephin, and TGF beta 1 did not induce motor axon outg rowth. Both GDNF and neurturin bind to Bet receptor complexes and were capa ble of activating the MAP kinase pathway. A specific inhibitor of MAP kinas e kinase, PD98059, inhibited the motor axon outgrowth-promoting activity of the GDNF but not the neuroprotective activity. Similarly, the specific PI3 K inhibitors, LY294002 and wortmannin, were able to inhibit the promotion o f motor axon outgrowth by GDNF, but did not affect neuroprotective activity . Our results suggest that the neurite outgrowth-promoting effect of GDNF i s mediated through the PI3K and MAP kinase pathways. The neuroprotective ef fect of GDNF appears to be through a separate pathway. (C) 2000 Academic Pr ess.