NGF- 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 signalling 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 upon BDNF withdrawal in sensory neurons. Our results indicate differences and similarities between the molecular signalling pathways behind NGF and BDNF deprivation-induced death. For instance, we observed that the inhibition of Trk receptors (K252a), PKC (Gö6976), protein translation (cycloheximide) or caspases (zVAD-fmk) provides protection from NGF deprivation-induced death but not from degeneration evoked by BDNF-withdrawal. Interestingly, degeneration of BDNF-dependent sensory neurons requires BAX and appears to rely on reactive oxygen species generation rather than caspases to induce degeneration. These results highlight the complexity and divergence of mechanisms regulating developmental sensory neuron death.

Significant statement The elimination of neuronal cells generated in excess during embryonic stages characterizes the maturation of the nervous system. Here we address the developmental cell death mechanisms of BDNF-dependent dorsal root ganglion neurons in vitro, comparing and contrast them with those deployed in NGF-dependent sensory neurons. We observe several important differences between the molecular signalling pathways behind NGF and BDNF deprivation-induced death. Significantly, degeneration of BDNF-dependent sensory neurons requires BAX but not caspase activation, instead reactive oxygen species generation appears to play a key role in degeneration. This work highlights the complexity of cell death mechanisms in distinct embryonic sensory neuron populations.