Although brain-derived neurotrophic factor (BDNF) has been shown to promote peripheral myelination during development and remyelination after injury, the precise mechanisms mediating this effect remain unknown. Here, we determine that BDNF promotes myelination of nerve growth factor-dependent neurons, an effect dependent on neuronal expression of the p75 neurotrophin receptor, whereas BDNF inhibits myelination of BDNF-dependent neurons via the full-length TrkB receptor. Thus, BDNF exerts contrasting effects on Schwann cell myelination, depending on the complement of BDNF receptors that are expressed by different subpopulations of dorsal root ganglion neurons. These results demonstrate that BDNF exerts contrasting modulatory roles in peripheral nervous system myelination, and that its mechanism of action is acutely regulated and specifically targeted to neurons.
Nerve cells require trophic signals transmitted from the nerve terminal via the axon in order to survive and develop normally. As the axon may be more than a meter long, specialised mechanisms are needed to transmit these signals. This involves the retrograde axonal transport of signalling endosomes containing nerve growth factor (NGF) and other synaptically derived molecules. These are large, double membrane multivesicular bodies containing a mixture of all vesicle types seen in the nerve terminal. How this signalling endosome is formed and targeted for retrograde axonal transport, however, remains an open question. Here we show that members of the Rab family of proteins that are retrogradely transported indicate that the signalling endosome contains both early and recycling endosomes. In addition, we show that retrogradely transported labelled antibody to dopamine beta-hydroxylase, a marker for synaptic vesicles, co-localizes within the same signalling endosome as NGF. We further show that LC3, a marker for autophagosomes, is retrogradely transported and associates with retrogradely transported NGF. We propose that neurons have exploited the mechanism of autophagy to engulf a sample of the cytoplasmic contents of the nerve terminal to transport back to the cell body. This sample of cytoplasmic contents relays a reliable snapshot of the totality of signalling events occurring in the nerve terminal at that instant in time.
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