The coming of age of axonal neurotrophin signaling endosomes

Abstract

Neurons of both the central and the peripheral nervous system are critically dependent on neurotrophic signals for their survival and differentiation. The trophic signal is originated at the axonal terminals that innervate the target(s). It has been well established that the signal must be retrogradely transported back to the cell body to exert its trophic effect. Among the many forms of transmitted signals, the signaling endosome serves as a primary means to ensure that the retrograde signal is delivered to the cell body with sufficient fidelity and specificity. Recent evidence suggests that disruption of axonal transport of neurotrophin signals may contribute to neurodegenerative diseases such as Alzheimer's disease and Down syndrome. However, the identity of the endocytic vesicular carrier(s), and the mechanisms involved in retrogradely transporting the signaling complexes remain a matter of debate. In this review, we summarize current insights that are mainly based on classical hypothesis-driven research, and we emphasize the urgent needs to carry out proteomics to resolve the controversies in the field.

Figure 1

A. A schematic representation of a nerve cell (adapted from learn.genetics.utah.edu/.../neuron_labeled.jpg). A typical neuron possesses an extensive network of dendrites and axons. The axon is often insulated with the myelin sheaths that are interrupted by the nodes of Ravier. The axon terminal innervates the target. The neurotrophic signal, released from the target, must be retrogradely transported to the cell body (soma). B: The different types of signaling endosomes. Neurotrophins such as NGF, are released from the target and bind to its Trk receptor at the axonal terminals. The ligand and receptor complex is internalized and is shuttled via the endocytic pathways. Endocytic compartments such as the early endosomes, MVBs and late endosomes have all been proposed to traffic the neurotrophic signal to the cell body. Through a different internalization pathway, macroendosomes may also be formed to carry the neurotrophin signals retrogradely.