NGF-dependent and BDNF-dependent DRG sensory neurons deploy distinct degenerative signaling mechanisms

Abstract

The nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are trophic factors required by distinct population of sensory neurons during development of the nervous system. Neurons that fail to receive appropriate trophic support are lost during this period of naturally occurring cell death. In the last decade, our understanding of the signaling pathways regulating neuronal death following NGF deprivation has advanced substantially. However, the signaling mechanisms promoting BDNF deprivation-induced sensory neuron degeneration are largely unknown. Using a well-established in vitro culture model of dorsal root ganglion (DRG), we have examined degeneration mechanisms triggered on BDNF withdrawal in sensory neurons. Our results indicate differences and similarities between the molecular signaling pathways behind NGF and BDNF deprivation-induced death. For instance, we observed that the inhibition of Trk receptors (K252a), PKC (Gö6976), protein translation (cycloheximide; CHX), or caspases (zVAD-fmk) provides protection from NGF deprivationinduced death but not from degeneration evoked by BDNF-withdrawal. Interestingly, degeneration of BDNFdependent sensory neurons requires BAX and appears to rely on reactive oxygen species (ROS) generation rather than caspases to induce degeneration. These results highlight the complexity and divergence of mechanisms regulating developmental sensory neuron death.