Endocytosis in the axon initial segment maintains neuronal polarity

Kelsie Eichel, Takeshi Uenaka, Vivek Belapurkar, Rui Lu, Shouqiang Cheng, Joseph S. Pak, Caitlin A. Taylor, Thomas C. Südhof, Robert Malenka, Marius Wernig, Engin Özkan, David Perrais and Kang Shen ()
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Kelsie Eichel: Stanford University
Takeshi Uenaka: Stanford University School of Medicine
Vivek Belapurkar: University of Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience
Rui Lu: Stanford University
Shouqiang Cheng: University of Chicago
Joseph S. Pak: University of Chicago
Caitlin A. Taylor: Stanford University
Thomas C. Südhof: Stanford University
Robert Malenka: Stanford University
Marius Wernig: Stanford University School of Medicine
Engin Özkan: University of Chicago
David Perrais: University of Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience
Kang Shen: Stanford University

Nature, 2022, vol. 609, issue 7925, 128-135

Abstract: Abstract Neurons are highly polarized cells that face the fundamental challenge of compartmentalizing a vast and diverse repertoire of proteins in order to function properly1. The axon initial segment (AIS) is a specialized domain that separates a neuron’s morphologically, biochemically and functionally distinct axon and dendrite compartments2,3. How the AIS maintains polarity between these compartments is not fully understood. Here we find that in Caenorhabditis elegans, mouse, rat and human neurons, dendritically and axonally polarized transmembrane proteins are recognized by endocytic machinery in the AIS, robustly endocytosed and targeted to late endosomes for degradation. Forcing receptor interaction with the AIS master organizer, ankyrinG, antagonizes receptor endocytosis in the AIS, causes receptor accumulation in the AIS, and leads to polarity deficits with subsequent morphological and behavioural defects. Therefore, endocytic removal of polarized receptors that diffuse into the AIS serves as a membrane-clearance mechanism that is likely to work in conjunction with the known AIS diffusion-barrier mechanism to maintain neuronal polarity on the plasma membrane. Our results reveal a conserved endocytic clearance mechanism in the AIS to maintain neuronal polarity by reinforcing axonal and dendritic compartment membrane boundaries.

Date: 2022
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DOI: 10.1038/s41586-022-05074-5

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