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Microtubule Plus-End Tracking Proteins in Neuronal Development

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Microtubule Plus-End Tracking Proteins in Neuronal Development Cell. Mol. Life Sci. (2016) 73:2053–2077 DOI 10.1007/s00018-016-2168-3 Cellular and Molecular Life Sciences REVIEW Microtubule plus-end tracking proteins in neuronal development 1 1 1 Dieudonne´e van de Willige • Casper C. Hoogenraad • Anna Akhmanova Received: 13 December 2015 / Revised: 4 February 2016 / Accepted: 22 February 2016 / Published online: 11 March 2016 Ó The Author(s) 2016. This article is published with open access at Springerlink.com Abstract Regulation of the microtubule cytoskeleton is AIS Axon initial segment of pivotal importance for neuronal development and BDNF Brain-derived neurotrophic factor function. One such regulatory mechanism centers on CAMSAP Calmodulin-regulated spectrin-associated microtubule plus-end tracking proteins (?TIPs): struc- protein turally and functionally diverse regulatory factors, which CAP-Gly Cytoskeletal-associated protein glycine-rich can form complex macromolecular assemblies at the CEP Centrosomal protein growing microtubule plus-ends. ?TIPs modulate important CFEOM1 Congenital fibrosis of the extraocular muscles properties of microtubules including their dynamics and type 1 their ability to control cell polarity, membrane transport CH Calponin homology and signaling. Several neurodevelopmental and neurode- CLASP Cytoplasmic linker protein-associated protein generative diseases are associated with mutations in ?TIPs CLIP Cytoplasmic linker protein or with misregulation of these proteins. In this review, we DRG Dorsal root ganglia focus on the role and regulation of ?TIPs in neuronal EB End-binding protein development and associated disorders. EFA-6 Exchange factor for Arf6 EM Electron microscopy Keywords Neuron Á Development Á Polarity Á ER Endoplasmic reticulum Cytoskeleton Á Microtubule Á Plus-end tracking proteins Á GAR Growth arrest-specific 2 protein-related region EB Á CLIP Á CLASP GSK3b Glycogen synthase kinase 3 beta HMN7B Hereditary motor neuropathy 7B Abbreviations MACF Microtubule-actin crosslinking factor Abi Abelson interacting protein MAP Microtubule-associated protein Abl Abelson kinase MCAK Mitotic centromere-associated kinesin AD Alzheimer’s disease MT Microtubule NAV Neuron navigator NMDA N-Methyl-D-aspartate PI3K Phosphoinositide 3-kinase SCA11 Spinocerebellar ataxia type 11 SOCE Store operated calcium entry STIM1 Stromal interaction molecule 1 & Casper C. Hoogenraad TDP-43 Transactive response DNA binding protein of [email protected] 43 kDa & Anna Akhmanova ?TIP Microtubule plus-end tracking protein [email protected] TOG Tumor overexpressed gene 1 Cell Biology, Faculty of Science, Utrecht University, TTBK Tau-tubulin kinase Padualaan 8, 3584 CH Utrecht, The Netherlands 123 2054 D. van de Willige et al. Introduction targeting by associating with specific parts of the MT lat- tice or by interacting with the soluble tubulin pool. Well- Microtubules (MTs) are one of the major types of filaments characterized neuronal MAPs include MAP2 and tau, that constitute the eukaryotic cytoskeleton. Over the years, which maintain a polarized, mutually exclusive distribution MTs have emerged as key players in cellular processes and decorate MT bundles in dendrites and axons, respec- such as vesicle and organelle transport, DNA segregation tively. Both proteins stabilize MTs and are able to induce during mitosis, cell migration and maintenance of cell MT bundling (reviewed in [8]). Abnormal phosphorylation polarity. Neurons are among the most complex and of tau triggers its dissociation from MTs and causes tau to polarized cells, whose distinct morphology allows them to aggregate, resulting in the formation of potentially toxic establish intercellular connections and propagate chemical tau deposits (neurofibrillary tangles) found in the brains of and electrical signals across the nervous system. Mature patients suffering from Alzheimer’s disease (AD) and other neurons typically extend multiple processes, one of which tauopathies. This process is accompanied by degradation of (the axon) serves as a transmitter whereas others (the the axonal MT cytoskeleton, suggesting a model in which dendrites) act as receivers of input from other neurons. dissociation of tau results in MT instability. It should be MTs are important for numerous functions in nerve cells noted, however, that the precise hierarchy of events during (reviewed in [1–3]), such as long-range transport of cargo the onset of AD remains unclear. Additional roles for tau and neuron-specific processes like growth cone guidance. are still emerging and may shed new light on the biology of Indeed, MTs are indispensable for neurodevelopment, and tauopathies (reviewed in [9]). Among these is the regula- many neurological diseases stem from defects in the MT tion of the subcellular distribution of MAPs that cytoskeleton or its regulation. specifically bind to the growing MT plus-end [10], the Evidence for the existence of MTs was first obtained subclass of MAPs that this review will focus on. from electron microscopy (EM) data in the 1950s (re- MT dynamics are most pronounced at the plus-end. viewed in [4]). Prior to the development of EM, fibrillar Although growth events have been observed at the MT structures had already been described as part of the mitotic minus-end [11], in cells minus-ends are often anchored or spindle and cytoplasm. However, interpretative differences stabilized, restricting their dynamic behavior [12]. At the and technical limitations of early microscopy made it growing plus-end, freshly polymerized MT stretches challenging to identify unity among observations [4]. It contain GTP-loaded b-tubulin as opposed to the GDP- therefore was not until 1963 that MTs were acknowledged bound subunits present in the MT lattice, resulting in a as distinct structures and named by Slautterback, Ledbetter so-called GTP cap. Moreover, the structures of poly- and Porter [5, 6]. Today, we know that MTs are hollow merizing and depolymerizing MT plus-ends are different tubes with a diameter of approximately 25 nm. MTs are [13]. The unique chemical environment of the polymer- typically assembled from 13 laterally associating protofil- izing MT plus-end grants it its own interactome within aments, which in turn consist of a, b-tubulin dimers the realm of MAPs, consisting of MT plus-end tracking aligned in a head-to-tail fashion. As a consequence of proteins (?TIPs;reviewedin[14–16]). ?TIPs display a tubulin dimer polarity, MTs possess polarity throughout, large structural and functional variation between indi- which results in distinct ends of the polymer: the minus- vidual proteins. However, a common theme sets them and the plus-end, exposing a- and b-tubulin, respectively. apart from other MAPs: ?TIPs associate with the poly- MTs alternate between rapid phases of growth and merizing MT plus-end, where they act as powerful shrinkage, a behavior termed ‘dynamic instability’ [7]. A regulators of MT dynamics and MT interactions with transition from shrinkage to growth is called a rescue, other structures. whereas the opposite transition is referred to as a In this review, we use the neuronal MT cytoskeleton to catastrophe. illustrate the role of ?TIPs in the development of one of Dynamic instability allows MTs to be swiftly remodeled the most polarized and complex cell types. Before dis- in response to environmental cues. The MT cytoskeleton is cussing plus-end tracking mechanisms and highlighting the suitable for rapidly sensing and responding to changes in roles and regulation of various ?TIPs in neurons, we touch the intracellular environment. To this end, the MT upon the function of the MT cytoskeleton in the developing cytoskeleton acts in concert with a large number of proteins and mature nervous system. Moreover, we highlight the (MAPs for MT-associated proteins) that either influence role of ?TIPs in neurodegenerative and neurodevelop- MTs themselves or relay signals from the MT cytoskeleton mental diseases. We conclude this review with an outlook to other parts of the cell. MAPs are known to regulate MT on the future of neuronal ?TIP research and briefly discuss behavior such as stability, assembly, bundling and the drug target potential of these pivotal proteins. 123 Microtubule plus-end tracking proteins in neuronal development 2055 Microtubules in neurons drives invasion of the extracellular matrix (reviewed in [25]), an array of MTs controls the direction in which the Neurons are derived from progenitor cells located in the growth cone advances (Fig. 1d; [26]). The MT array ventricular zone deep inside the brain, necessitating young assumes a looped conformation in pausing growth cones neurons to migrate large distances into remote regions. [27], while active growth cones maintain a dynamic MT During their journey, neurons undergo dramatic changes in array. These MTs probe the growth cone cortex and morphology and establish complex polarity. Even mature respond to guidance signals by being stabilized or desta- neurons must remain plastic as connections between neu- bilized, prompting the growth cone to turn towards or away rons, synapses, are continuously rewired in response to from the guidance cue, respectively [24, 28]. As the axon stimuli. This intricate development relies heavily on both matures further, it branches to allow higher interconnec- the MT and the actin cytoskeleton, on their crosstalk and tivity. Branch formation is accomplished by splaying of on their accessory proteins. For a detailed analysis of the tau-decorated MT bundles at branching sites. Here, role of the cytoskeleton and in particular MTs
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