Retrogradely Transported TrkA Endosomes Signal Locally within Dendrites to Maintain Sympathetic Neuron Synapses

Abstract

Summary Sympathetic neurons require NGF from their target fields for survival, axonal target innervation, dendritic growth and formation, and maintenance of synaptic inputs from preganglionic neurons. Target-derived NGF signals are propagated retrogradely, from distal axons to somata of sympathetic neurons via TrkA signaling endosomes. We report that a subset of TrkA endosomes that are transported from distal axons to cell bodies also translocate into dendrites, where they are signaling-competent and move bidirectionally, in close proximity to synaptic protein clusters. Using a strategy for spatially-confined inhibition of TrkA kinase activity, we found that distal axon-derived TrkA signaling endosomes are necessary specifically within sympathetic neuron dendrites for maintenance of synapses. Thus, TrkA signaling endosomes have unique functions in different cellular compartments. Moreover, target-derived NGF mediates circuit formation and synapse maintenance through TrkA endosome signaling within dendrites to promote aggregation of postsynaptic protein complexes.

BDNF/TrkB signaling endosomes in axons coordinate CREB/mTOR activation and protein synthesis in the cell body to induce dendritic growth in cortical neurons

“…In the second possibility, BDNF retrograde signaling promotes the phosphorylation of somatodendritic TrkB receptors, and this process is required to maintain CREB phosphorylation. In agreement with this last idea, other groups have shown that retrogradely transported TrkA in sympathetic neurons accumulates in the somatodendritic compartment locally, increasing the phosphorylation of other TrkA receptors in dendrites and cell body (Lehigh et al, 2017;Yamashita et al, 2017).…”

Sympathetic tales: subdivisons of the autonomic nervous system and the impact of developmental studies

“…In addition to the importance of NGF for innervation of sympathetic target tissues, this growth factor is critical for development of the dendritic arbor of the neurons [ 120 ]. In addition, the development of the synaptic connections between preganglionic and postganglionic sympathetic neurons depends on NGF [ 121 ] where activated trkA receptors are required in the dendritic compartment of the postganglionic neurons to maintain the synaptic connections with the preganglionic input [ 122 ] (see also below).…”

The many disguises of the signalling endosome

“…Nevertheless, some of the functions in dendrites require the integrated control of local and global signalling, a matter that has been recently addressed by the Ginty's group by showing that in sympathetic neurons, a pool of retrogradely transported signalling endosomes were found in dendrites ( Fig. 1G) and in close proximity to synapses [84]. Importantly, the majority of these organelles (~80%) remained mobile, whilst the somabound endosomes are less dynamic, suggesting that these organelles are different [84].…”

“…Indeed, a subpopulation of NGF-TrkA signalling endosomes originated in distal axons of postganglionic neurons, are retrogradely transported into dendrites, where TrkAdependent MAPK activity induces postsynaptic density clustering. Activation of TrkA in axonal signalling endosomes is also essential for the maintenance of synapses between pre-and postganglionic neurons, both in vitro and in vivo [84,85]. Taken together, the control of target innervation, and synapse formation and maintenance, exemplify how retrograde neurotrophic signalling regulates network formation in the nervous system, a topic reviewed elsewhere [86,87].…”

“…Internalisation of receptors is crucial not only for long distance propagation of neurotrophic effects, but also for engaging intracellular interactors enabling the activation of distinct signalling pathways [15,124]. It is critical for local effects relying on the accumulation of signalling molecules at specific locations, as in the case of synaptic assembly sites, branching points on neurites and the leading edge of a migrating precursor [51,53,84,85,125]. Specific mechanisms of internalisation have proved to be particularly important for generating intracellular compartments with distinct signalling capabilities.…”