The Neuronal Endosomal System and its Functions in Trafficking L1/NgCAM
Lasiecka, Zofia Maria, Department of Neuroscience, University of Virginia
Lee, Kevin, Department of Neuroscience, University of Virginia
Winckler, Bettina, Department of Neuroscience, University of Virginia
Correct targeting of proteins to the axons and dendrites is crucial for neuronal function. Endosomal system plays important role in targeting proteins, and thereby it participates in various neuronal functions such as neurite outgrowth and synaptic plasticity. The neuronal endosomal system is different from the canonical endosomal system due to the unique neuronal role and morphology. Neurons contain canonical endosomal proteins such as EHD1 (Eps15 homology-domain containing protein 1) and EEA1 (early endosome antigen 1). In non-neuronal cells, EHD1 functions in the recycling endosome and is required for endosome-to-plasma membrane transport of multiple cargos. EEA1 is localized to early endosomal compartments, functions in homophilic early endosome fusion, and is important in trafficking of transferrin and EGFR in non-neuronal cells. It is not known whether those canonical endosome regulators have the same functions in neurons as in non-neuronal cells. Neurons also express neuronal-specific endosomal protein NEEP21 (neuron-enriched endosomal protein of 21kD), which is important in trafficking of AMPAR. We showed previously that axonal accumulation of the cell adhesion molecule L1/NgCAM depends on somatodendritic endocytosis. We show here that axonal accumulation of L1/NgCAM occurs via somatodenritic early endosomes and depends on EHD1, EEA1, and NEEP21 endosomal regulators. Interestingly, we demonstrate that, in contrast to non-neuronal cells, EHD1 in neurons is localized mostly to EEA1-positive early endosomes. In contrast NEEP21-positive early endosomes mostly do not colocalize with EEA1-positive canonical early endosomes. Live imaging show that EEA1, EHD1, and NEEP21 each have distinct motile behavior, however they can dynamically interact with each other., which suggest that they can work together in cargo sorting. Down-regulation or interference with any of those regulators leads to missorting of L1/NgCAM to the somatodenritic surface and accumulation of L1/NgCAM in somatodendritic endosomes. Finally, down-regulation of NEEP21 or interference with EEA1 cause inhibition of L1- mediated axon outgrowth. These findings point to the existence of neuronal adaptations of early endosomes and the importance of somatodendritic endosomal trafficking of L1/NgCAM in L1-mediated axon outgrowth.
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PHD (Doctor of Philosophy)
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