Action in the axon: generation and transport of signaling endosomes

Abstract

Neurons extend axonal processes over long distances, necessitating efficient transport mechanisms to convey target-derived neurotrophic survival signals from remote distal axons to cell bodies. Retrograde transport, powered by dynein motors, supplies cell bodies with survival signals in the form of 'signaling endosomes'. In this review, we will discuss new advances in our understanding of the motor proteins that bind to and move signaling components in a retrograde direction and discuss mechanisms that might specify distinct neuronal responses to spatially restricted neurotrophin signals. Disruption of retrograde transport leads to a variety of neurodegenerative diseases, highlighting the role of retrograde transport of signaling endosomes for axonal maintenance and the importance of efficient transport for neuronal survival and function.

Figure 1

Signaling endosomes are transported retrogradely from distal axons to neuronal cell bodies by the motor protein dynein along microtubules. NGF is released from target tissues, where it binds to and activates TrkA receptors at the nerve terminal. Ligand-receptor complexes are endocytosed into signaling endosomes and transported retrogradely in association with downstream signaling components. These downstream components help identify the spatial location of neurotrophin signaling events. Spatially selective signaling components include phosphorylated Erk5 and NGF-induced axonally translated CREB. Upon arrival at the cell body, translocation of signaling components to the nucleus activates a set of transcription factors to mediate target-derived NGF-dependent responses. CREB induces a set of genes necessary for survival, while SRF induces a set of genes to mediate axonal outgrowth and target innervation.

Figure 2

Proteins are transported along the microtubules anterogradely and retrogradely by kinesins and dyneins, respectively. Post-translational modifications such as sumoylation can specify directionality of transport in the case of the RNA-binding protein La. La binds to kinesin and is anterogradely transported in the absence of sumoylation; when sumoylated, La binds to dynein and is retrogradely transported. Specificity of cargo binding for retrograde transport can be achieved through differential isoforms of dynein subunits. The neuron-specific intermediate chain IC-1B selectively binds to and transports TrkB-containing signaling endosomes, while the ubiquitously expressed IC-2C does not.