DISTINCT MODULATORY ACTIONS OF TGF-BETA AND LIF ON NEUROTROPHIN-MEDIATED SURVIVAL OF DEVELOPING SENSORY NEURONS

The neurotrophins nerve growth factor (NGF), brain-derived neurotrophi c factor (BDNF), and neurotrophin-3 (NT-3) are important for the regul ation of survival and differentiation of distinct, largely non-overlap ping populations of embryonic sensory neurons. We show here that the m ultifunctional cytokine transforming growth factor-beta (TGF-beta) fai ls to maintain sensory neurons cultured from embryonic day (E) 8 chick dorsal root ganglia (DRG), although DRG neurons are immunoreactive fo r the TGF-beta receptor type II, which is essential for TGF-beta signa ling. However, in combination with various concentrations of NT-3 and NT-4, but not NGF, TGF-beta 3 causes a further significant increase in neuron survival. In DRG cell cultures treated with NGF, NT-3, and NT- 4, a neutralizing antibody to TGF-beta decreases neuron survival sugge sting that endogenous TGF-beta in these cultures affects the efficacie s of neurotrophins. Consistent with this notion and a modulatory role of TGF-beta in neurotrophin functions is the observation that TGF-beta 2 and -beta 3 immunoreactivities and TGF-beta 3 mRNA are located in e mbryonic chick DRG in close association with neurons from E5 onwards. We also show that leukemia inhibitory factor (LIF) significantly decre ases NGF-mediated DRG neuron survival. Together, these data indicate t hat actions and efficacies of neurotrophins are under distinct control by TGF-beta and LIF in vitro, and possibly also in vivo.