Elsevier

Molecular and Cellular Neuroscience

The third wave: Intermediate filaments in the maturing nervous system

Abstract

Intermediate filaments are critical for the extreme structural specialisations of neurons, providing integrity in dynamic environments and efficient communication along axons a metre or more in length. As neurons mature, an initial expression of nestin and vimentin gives way to the neurofilament triplet proteins and α-internexin, substituted by peripherin in axons outside the CNS, which physically consolidate axons as they elongate and find their targets. Once connection is established, these proteins are transported, assembled, stabilised and modified, structurally transforming axons and dendrites as they acquire their full function. The interaction between these neurons and myelinating glial cells optimises the structure of axons for peak functional efficiency, a property retained across their lifespan. This finely calibrated structural regulation allows the nervous system to maintain timing precision and efficient control across large distances throughout somatic growth and, in maturity, as a plasticity mechanism allowing functional adaptation.

Introduction

Intermediate filaments (IFs) are cytoskeletal components of all eukaryotes, which in vertebrates and many invertebrates (Lasek et al., 1985, Parry, 2011, Herrmann and Strelkov, 2011, Wang and Szaro, 2016) have been adapted to meet the challenges of maintaining axons thousands of times longer than the processes of other cells (see Perrot and Eyer, 2013, for review). Their role in the developing nervous system is one of structural consolidation – although some neuronal intermediate filaments (NIFs) are present and active during early differentiation and neurite growth, their chief function is realised when dense arrays of phosphorylated NIFs fill and transform the cytoplasm of mature axons. This is not always a simple progression to stable maturity: NIF networks can be dynamic, and change state in response to endogenous and exogenous factors, including active myelination and demyelination processes used by the central nervous system to sculpt its functional efficiency. If neural development can be considered as a phase of neurogenesis and gliogenesis, followed by a surge of neurite outgrowth, guidance and connection, then the mass deployment of NIFs represents a third wave of structural maturation, enabling myelination and mature plasticity.

Throughout the lifespan, NIFs are dynamic cytoskeletal elements subject to a range of post-translational modifications, primarily phosphorylation and glycosylation (Snider and Omary, 2014), and are implicated in the pathogenesis and progression of a range of nervous system diseases (Gentil et al., 2015). This review focuses on the initial expression and deployment of NIFs in the developing nervous system, for which the great majority of gene expression and regulation data, along with much of the chemoarchitectonic anatomical characterisation, derive from rodent studies. Although there is considerable homology between the NIFs of mammal species (Lee et al., 1986, UniProt Consortium, 2017), where possible data from other species including primates are cited, and differences between rodents and primates are noted.

Section snippets

The intermediate filaments of the nervous system

Aside from the membrane-scaffolding actin-spectrin network and the major transport and mechanical roles played by microtubules (MTs), a third class of cytoskeletal element allows neurons to structure their cytoplasm, particularly in the axon (Weiss and Mayr, 1971). These intermediate filaments are long protein polymers with a diameter between those of actin filaments and MTs. Five basic types of IFs are recognised based on sequence homology (Parry, 2011), and most neuronal intermediate

Developmental regulation and expression timecourse of NIFs

NIFs are expressed during the differentiation and development of the nervous system, in a pattern which is strongly phylogenetically conserved among vertebrates, although specifics differ between various CNS and PNS structures (Julien et al., 1986, Nixon and Shea, 1992, Kure and Brown, 1995, Szaro and Strong, 2011). Expression of nestin, then vimentin is ubiquitous in neuron precursors of the neural tube and, in humans, neural crest (Ziller et al., 1983, Cochard and Paulin, 1984, Lendahl et

Plasticity beyond development

Beyond the complex task of establishing and optimising the signal paths of the nervous system, the axonal cytoskeleton needs to adapt to the enormous functional changes imposed by growth and aging across decades of life. The length and path of peripheral axons changes with growth and maturity, and both the utility of somatosensory inputs and the efficient control of muscles require accurate and consistent timing of signal transduction across distances up to metres in scale. Although human

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