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 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 (ROS) generation rather than caspases to induce degeneration. These results highlight the complexity and divergence of mechanisms regulating developmental sensory neuron death.
Highlights
The developing nervous system undergoes a period of neuronal cell death during embryogenesis
The extent and density of neurites was maximal at a brain-derived neurotrophic factor (BDNF) concentration of 125 ng/ml (Fig. 2A), but even at this concentration, processes were significantly less dense and shorter than within parallel dorsal root ganglion (DRG) cultured in nerve growth factor (NGF)
It was noted that DRGs derived from the lumbar and cervical parts of the spinal cord extended more exuberant processes in response to BDNF than DRGs derived from the thoracic region (Fig. 2B)
Summary
The developing nervous system undergoes a period of neuronal cell death during embryogenesis 2000; Buss et al, 2006; Schuldiner and Yaron, 2015). In this period, neurons that fail to receive trophic support die by apoptosis (Burek and Oppenheim, 1996), a type of cell. Diverse sub-types of sympathetic and sensory neurons develop, compete, survive, or die based on their capacity to bind enough trophic support from their target tissue (Barde, 1989; Saxena and Caroni, 2007)
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