Molecular-Scale Dynamics of Long Range Retrograde Brain-Derived Neurotrophic Factor Transport Shaped by Cellular...

Retrograde neurotrophin (NT) transport is a specialized form of signal transduction used to conduct information from axons to the cell bodies of central and peripheral nervous system neurons. It is activated upon NT-Trk receptor binding, NT-Trk internalization into signaling endosomes, and their motion along the axon toward the cell body. Brain-derived neurotrophic factor (BDNF) is an abundant NT that modulates key brain and spinal cord functions, and defects in BDNF trafficking are associated with neuronal death, neurodegenerative diseases and in nerve injury. Decades of study have yielded impressive progress in elucidating NT retrograde transport; however, much information remains unclear. For example, while it is known that NT function is dependent on tight control of NT-receptor intracellular trafficking, data describing the precise spatiotemporal molecular dynamics of their axonal to somatic transport are lacking. In past work, we showed the use of discrete, photo-bleaching-resistant quantum dot (QD)-BNDF probes to activate and track BDNF-TrkB receptor internalization; this revealed a rich diversity of molecular motions that intracellular BDNF signaling endosomes undergo within the soma of nodose ganglia sensory neurons. Here, we used combined techniques of discrete QD-BDNF tracking with compartmented microfluidic chambers to characterize retrograde BDNF-TrkB transport over long-ranging distances of primary dorsal root ganglion sensory neuronal axons. Our new findings show that axonal retrograde motion is comprised of heterogeneous mixtures of diffusive behaviors, pauses, and variations in net molecular-motor-dependent transport speeds. Notably, specific molecular dynamic features such as NT speed were dependent on spatial context that could be categorized in distance from distal axons and proximity to the soma and were not entirely dictated by active motor transport speed. The important implication is recognition that NT-receptor retrograde transport is comprised of molecular dynamics, which change over the course of long-range trafficking to shape overall transport and possibly signaling.