Spatiotemporal Intracellular Dynamics of Neurotrophin and Its Receptors. Implications for Neurotrophin Signaling and Neuronal Function

Abstract

Neurons possess a polarized morphology specialized to contribute to neuronal networks, and this morphology imposes an important challenge for neuronal signaling and communication. The physiology of the network is regulated by neurotrophic factors that are secreted in an activity-dependent manner modulating neuronal connectivity. Neurotrophins are a well-known family of neurotrophic factors that, together with their cognate receptors, the Trks and the p75 neurotrophin receptor, regulate neuronal plasticity and survival and determine the neuronal phenotype in healthy and regenerating neurons. Is it now becoming clear that neurotrophin signaling and vesicular transport are coordinated to modify neuronal function because disturbances of vesicular transport mechanisms lead to disturbed neurotrophin signaling and to diseases of the nervous system. This chapter summarizes our current understanding of how the regulated secretion of neurotrophin, the distribution of neurotrophin receptors in different locations of neurons, and the intracellular transport of neurotrophin-induced signaling in distal processes are achieved to allow coordinated neurotrophin signaling in the cell body and axons.

Cellular and molecular mechanisms regulating neuronal growth by brain‐derived neurotrophic factor

“…These endosomes are likely different from the TrkA‐positive endosomes because p75 has different kinetics of internalization compared with TrkA [Bronfman et al, ; McCaffrey et al, ]. In contrast to what has been observed for the Trks, p75 is poorly targeted to the degradative pathway (i.e., late endosomes and lysosomes) [Bronfman et al, ]. We have shown that after internalization in PC12 cells and sympathetic neurons, p75 accumulates in the recycling endosomes and multivesicular bodies (MVB) and is ready for exosomal release, which is a ligand‐dependent process; therefore, increased internalization augmented the p75 content in exosomes after neuronal depolarization [Escudero et al, ].…”

“…It was later shown that neurotrophins have multiple functions in the CNS including regulation of neuronal morphology and plasticity. Over the last few years, it has been shown that neurotrophins can be secreted from different types of cells including neurons to stimulate paracrine and autocrine actions [Bronfman et al, , and references therein].…”

“…After ligation, the neurotrophin/receptor complex rapidly activates signaling pathways in the plasma membrane and undergoes internalization. It is now well established that the internalization and post‐endocytic trafficking of receptors are essential for signaling and neuronal function [Bronfman et al, , and the references therein].…”

Macromolecular transport in synapse to nucleus communication

“…Finally, it will be interesting to find out whether signaling endosomes might also play a role in synapse to nucleus signaling, analogous to their well-established role in survival and maintenance signaling in the axonal compartment [98,99]. A recent study used microfluidics chambers to investigate dendrite to nucleus signaling in embryonic cortical neurons, demonstrating that dendritic application of BDNF elicited a transcriptional response in the soma [100].…”

Analysis of Important Gene Ontology Terms and Biological Pathways Related to Pancreatic Cancer

“…During the initiation and progression of pancreatic cancer, ERBB signaling pathway has been confirmed to participate in the biological processes, validating our newly presented algorithm [83]. Neurotrophins have firstly been identified as a group of proteins that contribute to the survival, development, and function of neurons [84]. However, recent publications have revealed that neurotrophins may participate in the survival and proliferation of various cell types including the tumor cells [85–87].…”