The many disguises of the signalling endosome

Abstract

Neurons are highly complex and polarised cells that must overcome a series of logistic challenges to maintain homeostasis across their morphological domains. A very clear example is the propagation of neurotrophic signalling from distal axons, where target-released neurotrophins bind to their receptors and initiate signalling, towards the cell body, where nuclear and cytosolic responses are integrated. The mechanisms of propagation of neurotrophic signalling have been extensively studied and, eventually, the model of a 'signalling endosome', transporting activated receptors and associated complexes, has emerged. Nevertheless, the exact nature of this organelle remains elusive. In this Review, we examine the evidence for the retrograde transport of neurotrophins and their receptors in endosomes, outline some of their diverse physiological and pathological roles, and discuss the main interactors, morphological features and trafficking destinations of a highly flexible endosomal signalling organelle with multiple molecular signatures.

Keywords: axonal transport; endosomes; neurotrophins; signalling.

Figure 1

Retrograde neurotrophic signalling organelles and their main destinations after arrival to the cell body. Different types of signalling endosomes and their cellular destinations have been displayed on the top of a camera lucida trace of a mouse primary motor neuron in culture. The type of carriers and their sequential trafficking steps emerge from evidence collected using diverse experimental models, such as sensory, sympathetic, and motor neurons. Whether they are all present in every neuronal subtype is currently unknown. After being released by the target tissue, NGF and BDNF bind to TrkA (A) and TrkB (A’) respectively, triggering their phosphorylation and internalisation. TrkA‐NGF (B) and TrkB‐BDNF (B’) complexes enter the endocytic pathway and reach the early endosome, an organelle characterised by the presence of Rab5. Retrograde transport of Rab5‐positive carriers of TrkA‐NGF complex has been shown (thick arrow in B). Activated receptors are then sorted into a late endosome compartment (C), characterised by the presence of Rab7. This compartment can undergo retrograde axonal transport towards the soma, or progress along the endolysosomal route maturing into a multivesicular body (MBV; D), which contains both Rab7 and CD63. MVBs can also transport both receptor‐ligand complexes to the cell soma. In addition, autophagosomes have also been reported as retrograde carriers for TrkB‐BDNF (E). We have not included the origin of the autophagosome in the axonal tip, since it is still a matter of debate. After signalling endosomes reach the soma, there are sorted into a variety of destinations. Several lines of evidence indicate that neurotrophin receptors are delivered to somatic MVBs (F). TrkB‐BDNF in MVBs or single‐membrane vesicles can be either delivered to the plasma membrane or targeted to lysosomes for degradation (G). A subpopulation of TrkA‐NGF positive cargoes has been shown to be transported into dendrites (H), where it regulates synapse formation and maintenance. TrkA‐NGF complexes can also be recycled to the soma plasma membrane, where they might activate naïve TrkA receptors (I) and induce their recruitment to the anterograde axonal transport route in Rab11‐positive organelles (J). The activity of the endoplasmic reticulum‐resident phosphatase PTP1B is required to ensure that no activated TrkA is sorted into axons. In parallel, a pool of newly synthesised TrkA receptor is anterogradely transported in secretory vesicles characterised by the presence of Rab27, CRMP2 and Slp1 (K).