Cytoskeletal organization of axons in vertebrates and invertebrates

Abstract

The maintenance of axons for the lifetime of an organism requires an axonal cytoskeleton that is robust but also flexible to adapt to mechanical challenges and to support plastic changes of axon morphology. Furthermore, cytoskeletal organization has to adapt to axons of dramatically different dimensions, and to their compartment-specific requirements in the axon initial segment, in the axon shaft, at synapses or in growth cones. To understand how the cytoskeleton caters to these different demands, this review summarizes five decades of electron microscopic studies. It focuses on the organization of microtubules and neurofilaments in axon shafts in both vertebrate and invertebrate neurons, as well as the axon initial segments of vertebrate motor- and interneurons. Findings from these ultrastructural studies are being interpreted here on the basis of our contemporary molecular understanding. They strongly suggest that axon architecture in animals as diverse as arthropods and vertebrates is dependent on loosely cross-linked bundles of microtubules running all along axons, with only minor roles played by neurofilaments.

Tau, XMAP215/Msps and Eb1 co-operate interdependently to regulate microtubule polymerisation and bundle formation in axons

“…As another example, we found that loss of either Eb1, XMAP215/Msps or Tau all caused a reduction in comet numbers, potentially reflecting changes in MT nucleation activity, consistent with reports of nucleation-promoting roles of XMAP215 (Flor-Parra, Iglesias-Romero et al, 2018, Roostalu, Cade et al, 2015, Thawani, Kadzik et al, 2018, Wieczorek, Bechstedt et al, 2015. Extending work from MT polymerisation to nucleation is possible in the fly system and would have the potential to deliver explanations for how numbers of MTs can be regulated in reproducible, neuron-specific ways, thus addressing a fundamental aspect of axon morphology (Prokop, 2020).…”

“…We propose that similar mechanisms might operate in smaller diameter axons in vertebrates, such as in parallel fibres of the cerebellum where Tau has demonstrated structural roles (Harada, Oguchi et al, 1994); they might explain the aforementioned findings of small Eb protein comets in cultured vertebrate neurons, as well as the reduction in MT numbers observed upon loss of Tau in C. elegans (Krieg, Stühmer et al, 2017). However, in larger diameter axons of vertebrates where MT densities are low (Prokop, 2020), the Eb1 depletion effect might be far less noticeable.…”

“…Understanding the machinery of MT polymerisation is of utmost importance in axons where MTs form loose bundles of enormous lengths which are essential for axonal morphogenesis and serve as life-sustaining transport highways (Prokop, 2020). They have to be maintained in functional state for up to a century in humans (Hahn et al, 2019).…”

Molecular and Cellular Mechanisms Affected in ALS

“…Neurofilaments are neuron-specific intermediate filaments that are stretch-resistant and are major cytoskeleton proteins [ 114 ]. They form parallel coiled-coiled heterotetramers composed of light, medium, and heavy-weighted neurofilaments (NF-L, NF-M, and NF-H, respectively) and α-internexin or peripherin [ 112 , 114 ]. Eight heterotetramers form cylindrical structures known as unit-length filaments (ULFs) with the tail domains sticking out [ 112 , 114 ].…”

“…They form parallel coiled-coiled heterotetramers composed of light, medium, and heavy-weighted neurofilaments (NF-L, NF-M, and NF-H, respectively) and α-internexin or peripherin [ 112 , 114 ]. Eight heterotetramers form cylindrical structures known as unit-length filaments (ULFs) with the tail domains sticking out [ 112 , 114 ]. A series of ULFs form a filament that matures into neurofilament after a radial compaction of the cylindrical structure [ 112 ].…”