Abstract
The axon initial segment (AIS) is a specialized structure in neurons that resides in between axonal and somatodendritic domains. The localization of the AIS in neurons is ideal for its two major functions: it serves as the site of action potential firing and helps to maintain neuron polarity. It has become increasingly clear that the AIS cytoskeleton is fundamental to AIS functions. In this review, we discuss current understanding of the AIS cytoskeleton with particular interest in its unique architecture and role in maintenance of neuron polarity. The AIS cytoskeleton is divided into two parts, submembrane and cytoplasmic, based on localization, function, and molecular composition. Recent studies using electron and subdiffraction fluorescence microscopy indicate that submembrane cytoskeletal components (ankyrin G, βIV-spectrin, and actin filaments) form a sophisticated network in the AIS that is conceptually similar to the polygonal/triangular network of erythrocytes, with some important differences. Components of the AIS cytoplasmic cytoskeleton (microtubules, actin filaments, and neurofilaments) reside deeper within the AIS shaft and display structural features distinct from other neuronal domains. We discuss how the AIS submembrane and cytoplasmic cytoskeletons contribute to different aspects of AIS polarity function and highlight recent advances in understanding their AIS cytoskeletal assembly and stability.
Highlights
Neurons are highly polarized cells that form the basis of directed information flow within the nervous system
The axon initial segment (AIS) cytoskeleton has a unique structure in the proximal axon
We focused on the cytoskeletal architecture of two distinct regions of the AIS, beneath the plasma membrane and within the cytoplasm, and discussed how they contribute to the role of the AIS in maintaining neuron polarity
Summary
Neurons are highly polarized cells that form the basis of directed information flow within the nervous system. The functional and morphological polarity of neurons depend on the asymmetric distribution of specific molecules to the axonal and somatodendritic domains. For the long-term maintenance of neuronal function and shape, axons and dendrites must retain their unique molecular components throughout the life of the organism. The AIS is uniquely positioned in the proximal axon, adjacent to and distal from the axon hillock, where it serves two functions: (1) to integrate synaptic inputs and generate action potentials and (2) to maintain neuron polarity. The AIS contributes to the maintenance of neuron polarity in at least two ways: first, it serves as a submembrane diffusion barrier that restricts the mobility of plasma membrane components, preventing them from passing from one domain to another [5, 6]; and second, it acts as an intracellular selective filter for the transport of organelles and molecules between these domains through the cytoplasm. We end with a discussion of mechanisms of AIS cytoskeletal assembly and maintenance
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