Signaling Over Distances

Abstract

Neurons are extremely polarized cells. Axon lengths often exceed the dimension of the neuronal cell body by several orders of magnitude. These extreme axonal lengths imply that neurons have mastered efficient mechanisms for long distance signaling between soma and synaptic terminal. These elaborate mechanisms are required for neuronal development and maintenance of the nervous system. Neurons can fine-tune long distance signaling through calcium wave propagation and bidirectional transport of proteins, vesicles, and mRNAs along microtubules. The signal transmission over extreme lengths also ensures that information about axon injury is communicated to the soma and allows for repair mechanisms to be engaged. This review focuses on the different mechanisms employed by neurons to signal over long axonal distances and how signals are interpreted in the soma, with an emphasis on proteomic studies. We also discuss how proteomic approaches could help further deciphering the signaling mechanisms operating over long distance in axons.

Fig. 1.

Long distance signaling initiated by calcium after axon injury. Calcium influx following injury in distal is initiated by various factors including RyR and IP3 channels. The released calcium ion activates calpain, eventually enhancing the cleavage of vimentin, which sterically protects ERK from dephosphorylation and enables transport of phosphorylated ERKs from the injury site to the cell body. In the soma, phosphorylated ERKs may activate downstream signals such as ELK1. In addition, calcium ion outflow from axonal ER, which is organized by ER-microtubule-associated proteins REEPs, atlastin and spastin, via IP3R and RyR may induce ER stress after the injury, because the transient calcium depletion of the ER lumen leads to ER stress. In response to ER stress, the ER stress transducers including protein kinase R-like ER kinase (PERK), inositol requiring kinase 1 (IRE1) and activating transcription factor 6 (ATF6) activate downstream signals. The other ER stress transducer Luman is locally cleaved in response to ER stress. The processed N-terminal fragment retrogradely transported to promote axon regeneration. In the distal site, calcium release induces ROS production and also affects mitochondria. Mitochondrial calcium and ROS overload lead to activate mPTP, resulting in mitochondrial-derived apoptosis. The damaged axonal mitochondria is degraded by PTEN induced putative kinase 1 (PINK1) and Parkin-mediated mitophagy.

Fig. 2.

Molecular mechanism of axonal transport along microtubules. Microtubule-associated motor protein dynein and kinesin-1 drive the motility of vesicles, organelles, proteins, and RNA granules containing snRNP. Axon injury leads to the formation of the complex coordinated by importin α, importin β, dynactin, and adaptor proteins JIP3 and HAP1, which link molecular motors to retrogradely transported vesicles. Simultaneously, TTL-mediated increase in tyrosinated tubulin, DLK activation via calcium influx and calpain-regulated cleavage of vimentin trigger the retrograde motility of various proteins (DLK, JNK, STAT3, ERK, and ATF4), neurotrophins (BDNF and vascular endothelial growth factor (VEGF)) and its receptors (flk-1). Adaptor protein JIP1 dephosphorylated by dual specificity phosphatase 1 (DUSP1) binds to LC3 inserted in autophaosome followed by promoting retrograde transportation of autophagosome. The phosphorylation of several adaptor proteins such as JIP1 and Htt acts as directionally switch and drives the vesicles containing APP and BDNF toward distal axon. The other neurotrophins (NT-3 internalized in endosome with TrkC and VEGF) and its receptors (TrkB, p75 receptor and flk-1) are also anterogradely transported along the microtubule. Several pathogens including RVG and TeNT-Nidogen complex are internalized in distal site and retrogradely transported toward cell body through hijacking the signaling endosome system to elicit its toxic effects.

Fig. 3.

Epigenetic responses to axonally-derived signals. The arrival of axon-derived signals leads to changes in the neuronal epigenome. Calcium influx in distal axon promotes retrograde transport of phosphorylated ERK toward cell soma. In the soma, phosphorylated ERK activates p300/CBP-associated factor (P/CAF) nuclear translocation, where P/CAF promotes the acetylation of histones that correlate with active transcription. In addition, a retrograde calcium wave elicits nuclear export of HDAC3 and HDAC5, which results in increased histone acetylation and activation of the proregenerative transcriptional response to the injury. Phosphorylated HDAC5 is also anterogradely transported along where it promotes deacetylation of microtubule in proximity of the injury site.