Classical and novel directions in neurotrophin transport and research: anterograde transport of brain-derived neurotrophic factor by sensory neurons.

After the discovery of nerve growth factor, a classic model of neurotrophin action was developed. In this model, nerve endings compete for limited quantities of neurotrophic factors produced in neuronal target tissues. Neurotrophins are bound with high-affinity receptors expressed on the neuronal membrane and then endocytosed and retrogradely transported back to the cell body of responsive neurons. This classic model of target derived trophic support has been utilized to explain a wide range of trophic actions including effects on neuronal survival, terminal branching, and protein expression. However, a number of recent findings in the field of neurotrophin research cannot be explained using the classic model. In the peripheral nervous system (PNS), sensory neurons have been shown to contain mRNA for a member of the neurotrophin family, brain-derived neurotrophic factor (BDNF). Sensory neurons do not receive synaptic input so neurotrophin production by these cells does not fit into the classic target derived model. In contrast to target derived trophic support, BDNF produced by sensory neurons provides local autocrine and paracrine neurotrophic support in vitro. Furthermore, in vivo, sensory neurons transport BDNF in the anterograde direction away from the cell body, and opposite to the retrograde direction utilized in the classic model. Thus, out of necessity, a new direction for neurotrophin research has developed to study the production and anterograde transport of neurotrophins. The importance of this new mode of neurotrophin action in the PNS is indicated by results that implicate it in the response to pain, inflammation, and nerve injury.