![]() We used this neuron to identify hallmarks of an AIS in C. The PVD neuron is exceptionally polarized and extends a highly branched dendrite and, by stark contrast, a single unbranched axon (Fig. elegans PVD sensory neuron as an in vivo model to study neuronal polarity with single-cell resolution in living animals. To investigate AIS function in neuronal polarity, we developed the C. We find that endocytic clearance of polarized receptors from the AIS membrane is conserved and used by diverse polarized receptors. Here, we describe a distinct and active mechanism by which polarized transmembrane proteins are removed from the AIS plasma membrane through endocytosis and degraded to maintain their axonal or dendritic compartmentalization. However, the mechanisms by which the AIS maintains the stringent compartmentalization of transmembrane proteins between the contiguous axonal and dendritic plasma membrane of the neuron remain unresolved. ![]() The currently known functions of the AIS in neuronal polarity fall into two general categories: (1) intracellular sorting that regulates vesicle transport 3, 11, 12, 13, 14, 15, 16, 17, 18, and (2) a diffusion barrier to slow the movement of axonal and dendritic proteins on the plasma membrane 19, 20, 21. The AIS is molecularly defined by ankyrinG, the AIS master organizer, and by a dense submembranous cytoskeletal network 9, 10. This extreme polarization underlies neuronal function, and loss of neuronal polarity is associated with neurological dysfunction and neurodegenerative diseases 5, 6, 7.Ī critical region for neuronal polarity is the AIS, a specialized boundary zone that separates the axonal and somato-dendritic domains 2, 8. To achieve this compartmentalization, neurons must sort and transport thousands of proteins to each domain and maintain their polarized distribution over the lifetime of the neuron 1. Neurons in particular are highly compartmentalized into distinct axonal and dendritic domains of 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.Ĭellular compartmentalization is a fundamental feature of eukaryotic cells, which enables them to organize biochemical reactions and create functional specializations 4. 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. 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. 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. How the AIS maintains polarity between these compartments is not fully understood. The axon initial segment (AIS) is a specialized domain that separates a neuron’s morphologically, biochemically and functionally distinct axon and dendrite compartments 2, 3. Neurons are highly polarized cells that face the fundamental challenge of compartmentalizing a vast and diverse repertoire of proteins in order to function properly 1.
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