title: Endocytosis and endosomes at the crossroads of regulating trafficking of axon outgrowth-modifying receptors.
abstract: In neurons, many receptors must be localized correctly to axons or dendrites for proper function. During development, receptors for nerve growth and guidance are targeted to axons and localized to growth cones where receptor activation by ligands results in promotion or inhibition of axon growth. Signaling outcomes downstream of ligand binding are determined by the location, levels and residence times of receptors on the neuronal plasma membrane. Therefore, the mechanisms controlling the trafficking of these receptors are crucial to the proper wiring of circuits. Membrane proteins accumulate on the axonal surface by multiple routes, including polarized sorting in the trans Golgi network, sorting in endosomes and removal by endocytosis. Endosomes also play important roles in the signaling pathways for both growth-promoting and -inhibiting molecules: signaling endosomes derived from endocytosis are important for signaling from growth cones to cell bodies. Growth-promoting neurotrophins and growth-inhibiting Nogo-A can use EHD4/Pincher-dependent endocytosis at the growth cone for their respective retrograde signaling. In addition to retrograde transport of endosomes, anterograde transport to axons in endosomes also occurs for several receptors, including the axon outgrowth-promoting cell adhesion molecule L1/NgCAM and TrkA. L1/NgCAM also depends on EHD4/Pincher-dependent endocytosis for its axonal polarization. In this review, we will focus on receptors whose trafficking has been reported to be modulated by the EHD4/Pincher family of endosomal regulators, namely L1/NgCAM, Trk and Nogo-A. We will first summarize the pathways underlying the axonal transport of these proteins and then discuss the potential roles of EHD4/Pincher in mediating their endocytosis.
authors.affiliation: Department of Neuroscience, University of Virginia Medical School, MR4-6115, 409 Lane Road Ext., Charlottesville, VA 22936, USA. bwinckler@virginia.edu
authors.forename: Bettina
authors.initials: B
authors.lastname: Winckler
authors.forename: Chan Choo
authors.initials: CC
authors.lastname: Yap
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D019062:Cell Adhesion Molecules, Neuron-Glia / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology*; D011992:Endosomes / Q000378:metabolism*; D020439:Growth Cones / Q000378:metabolism; D009185:Myelin Proteins / Q000378:metabolism; D009416:Nerve Regeneration / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D000070798:Nogo Proteins; D021381:Protein Transport / Q000502:physiology; D020917:Receptor, trkA / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D019062:Cell Adhesion Molecules, Neuron-Glia; C456611:Ehd4 protein, rat; D009185:Myelin Proteins; D009419:Nerve Tissue Proteins; D000070798:Nogo Proteins; C000603197:Rtn4 protein, rat; D020917:Receptor, trkA