Abstract
During the development of the sympathetic nervous system, signals from tropomyosin-related kinase receptors (Trks) and p75 neurotrophin receptors (p75) compete to regulate survival and connectivity. During this process, nerve growth factor (NGF)- TrkA signaling in axons communicates NGF-mediated trophic responses in signaling endosomes. Whether axonal p75 signaling contributes to neuronal death and how signaling endosomes contribute to p75 signaling has not been established. Using compartmentalized sympathetic neuronal cultures (CSCGs) as a model, we observed that the addition of BDNF to axons increased the transport of p75 and induced death of sympathetic neurons in a dynein-dependent manner. In cell bodies, internalization of p75 required the activity of JNK, a downstream kinase mediating p75 death signaling in neurons. Additionally, the activity of Rab5, the key GTPase regulating early endosomes, was required for p75 death signaling. In axons, JNK and Rab5 were required for retrograde transport and death signaling mediated by axonal BDNF-p75 in CSCGs. JNK was also required for the proper axonal transport of p75-positive endosomes. Thus, our findings provide evidence that the activation of JNK by p75 in cell bodies and axons is required for internalization to a Rab5-positive signaling endosome and the further propagation of p75-dependent neuronal death signals.
Highlights
Www.nature.com/scientificreports activation of c-jun N-terminal activated kinase (JNK), translocation of NFκB5–7 and nuclear accumulation of neurotrophin receptor-interacting factor (NRIF) are among those activated by p758
We investigated whether axonal p75 activation by BDNF is followed by neuronal degeneration, which is visualized as nuclear fragmentation, when the axons of CSCG are stimulated with BDNF
The binding of BDNF to p75 in the axons of sympathetic neurons increases the internalization and transport of the full-length p75 receptor to induce cell death in a dynein- and Rab5-dependent manner
Summary
Www.nature.com/scientificreports activation of c-jun N-terminal activated kinase (JNK), translocation of NFκB5–7 and nuclear accumulation of neurotrophin receptor-interacting factor (NRIF) are among those activated by p758. The NGF/activated TrkA signal competes with and silences a cell death signal induced by the binding of BDNF to p7512 Through this latter pathway, p75 signaling appears to impact the developing sympathetic nervous system by reducing the number of neurons and target innervation[13,14]. One possibility is that BDNF binding to axonal p75 receptors creates endosomes that retrogradely transport signals that induce the death of developing SCG neurons. We examined axonal p75 signaling using compartmentalized sympathetic neuronal cultures (CSCGs) and showed that axonally applied BDNF induced retrograde transport of p75 and apoptosis. Our results provide evidence that the activation of JNK induced by the binding of BDNF to p75 on axons increases the internalization of p75 into Rab5-positive organelles, an event that is required to propagate p75-induced death signaling to cell bodies. These findings are evidence that Rab5-positive signaling endosomes are required to propagate p75 death signaling
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