Differential effects of the trophic factors BDNF, NT-4, GDNF, and IGF-I on the isthmo-optic nucleus in chick embryos

The isthmo-optic nucleus (ION) of chick embryos is a model system for the study of retrograde trophic signaling in developing CNS neurons. The role of brain-derived neurotrophic factor (BDNF) is well established in this system. Recent work has implicated neurotrophin-4 (NT-4), glial cell line-derived neurotrophic factor (GDNF), and insulin-like growth factor I (IGF-I) as additional trophic factors for ION neurons. Here it was examined in vitro and in vivo whether these factors are target-derived trophic factors for the ION in 13- to 16-day-old chick embryos. Unlike BDNF, neither GDNF, NT-4, nor IGF-I increased the survival of ION neurons in dissociated cultures identified by retrograde labeling with the fluorescent tracer DiI. BDNF and IGF-I promoted neurite outgrowth from ION explants, whereas GDNF and NT-4 had no effect. Injections of NT-4, but not GDNF, in the retina decreased the survival of ION neurons and accelerated cell death in the ION. NT-4-like immunoreactivity was present in the retina and the ION. Exogenous, radiolabeled NT-4, but not GDNF or IGF-I, was retrogradely transported from the retina to the ION. NT-4 transport was significantly reduced by coinjection of excess cold nerve growth factor (NGF), indicating that the majority of NT-4 bound to p75 neurotrophin receptors during axonal transport. Binding of NT-4 to chick p75 receptors was confirmed in L-cells, which express chick p75 receptors. These data indicate that GDNF has no direct trophic effects on ION neurons. IGF-I may be an afferent trophic factor for the ION, and NT-4 may act as an antagonist to BDNF, either by competing with BDNF for p75 and/or trkB binding or by signaling cell death via p75.