p75 Is Required for the Establishment of Postnatal Sensory Neuron Diversity by Potentiating Ret Signaling

Producing the neuronal diversity required to adequately discriminate all elements of somatosensation is a complex task during organogenesis. The mechanisms guiding this process during dorsal root ganglion (DRG) sensory neuron specification remain poorly understood. Here, we show that the p75 neurotrophin receptor interacts with Ret and its GFRα co-receptor upon stimulation with glial cell line-derived neurotrophic factor (GDNF). Furthermore, we demonstrate that p75 is required for GDNF-mediated Ret activation, survival, and cell surface localization of Ret in DRG neurons. In mice in which p75 is deleted specifically within sensory neurons beginning at E12.5, we observe that approximately 20% of neurons are lost between P14 and adulthood, and these losses selectively occur within a subpopulation of Ret+ nonpeptidergic nociceptors, with neurons expressing low levels of Ret impacted most heavily. These results suggest that p75 is required for the development of the nonpeptidergic nociceptor lineage by fine-tuning Ret-mediated trophic support. [Display omitted] •The p75 neurotrophin receptor interacts with Ret and GFRα co-receptors•p75 enhances GFL signaling by modulating the level of Ret on the cell surface•Loss of p75 leads to defects in GFL-mediated survival of Ret-expressing neurons in vitro•p75 is required for the postnatal diversification of nonpeptidergic nociceptors The establishment of sensory neuron subpopulations is mediated by complex interactions between growth factors and transcription factors. Chen et al. demonstrate that the p75 neurotrophin receptor interacts with the GDNF receptor Ret, and this complex is required for the postnatal survival of nonpeptidergic nociceptive neurons by fine-tuning Ret-mediated trophic support.