Neuronal signaling through endocytosis

Abstract

The distinctive morphology of neurons, with complex dendritic arbors and extensive axons, presents spatial challenges for intracellular signal transduction. The endosomal system provides mechanisms that enable signaling molecules initiated by extracellular cues to be trafficked throughout the expanse of the neuron, allowing intracellular signals to be sustained over long distances. Therefore endosomes are critical for many aspects of neuronal signaling that regulate cell survival, axonal growth and guidance, dendritic branching, and cell migration. An intriguing characteristic of neuronal signal transduction is that endosomal trafficking enables physiological responses that vary based on the subcellular location of signal initiation. In this review, we will discuss the specialized mechanisms and the functional significance of endosomal signaling in neurons, both during normal development and in disease.

Figure 1.

Endocytosis in neurons. (A) Upon ligand binding, Trk receptors are activated and recruit PI3 kinase, Ras/MAPK, and PLC-γ to initiate downstream signaling pathways. (B) Internalization of neurotrophin/Trk complexes can occur via clathrin-dependent mechanisms to give rise to early endosomes, or via macropinocytosis, which gives rise to multivesicular bodies (MVBs). (C) The endosomal pathway involves maturation from early endosomes associated with Rab5 to late endosomes associated with Rab7. Vesicles are degraded in lysosomes or can be recycled back to the membrane through association with Rab11. (D) In neurons, endosomes are trafficked long distances along the axon by dynein-mediated retrograde transport toward the cell body, or by kinesin-mediated anterograde transport toward the distal axon.

Figure 2.

Internalization of Trk receptors is required for axon formation, elongation, and dendritic branching. (A) BDNF binding to TrkB activates cAMP and PKA to induce BDNF release and membrane insertion of TrkB. The increased BDNF-TrkB signaling activates PI3K to induce anterograde transport of TrkB to the membrane, creating a feed-forward autocrine loop that locally enhances BDNF signaling and promotes formation of an axon. (B) NGF-induced axon growth involves TrkA internalization. Signaling through PLC-γ, calcineurin, and dynamin1 promotes axon elongation independent of retrograde signaling and transcriptional responses. (C) BDNF induces dendritic branching that requires Rab11-dependent recycling of TrkB receptors.

Figure 3.

In Charcot-Marie Tooth disease type 2B, a mutant form of Rab7 impairs growth factor receptor endocytosis and signaling. (A) In PC12 cells, stimulation with EGF and NGF leads to activation of the Erk1/2 and p38 kinases and translocation of these kinases to the nucleus to activate the transcription factor Elk-1, and so promote gene expression of target genes required for axon growth and target innervation. (B) Expression of the CMT2B mutant form of Rab7 (mRab7) leads to increased pErk1/2 and p38 signaling owing to delayed trafficking of receptors to the lysosome for degradation. Mutant Rab7 attenuates the ability for Erk1/2 to translocate to the nucleus and so decreases expression of immediate early genes, c-fos and Egr-1.

Figure 4.

Huntingtin mediates retrograde transport of TrkB-BDNF signaling endosomes in dendrites of striatal neurons. (A) Huntingtin is required for association of TrkB and BDNF with dynein motors and for appropriate retrograde signals that lead to Erk activation and c-fos induction. (B) Mutant huntingtin prevents retrograde transport of TrkB and BDNF and so leads to degeneration of striatal neurons as observed in Huntington’s disease.