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      IKAP/Elp1 Is Required In Vivo for Neurogenesis and Neuronal Survival, but Not for Neural Crest Migration

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          Abstract

          Familial Dysautonomia (FD; Hereditary Sensory Autonomic Neuropathy; HSAN III) manifests from a failure in development of the peripheral sensory and autonomic nervous systems. The disease results from a point mutation in the IKBKAP gene, which encodes the IKAP protein, whose function is still unresolved in the developing nervous system. Since the neurons most severely depleted in the disease derive from the neural crest, and in light of data identifying a role for IKAP in cell motility and migration, it has been suggested that FD results from a disruption in neural crest migration. To determine the function of IKAP during development of the nervous system, we (1) first determined the spatial-temporal pattern of IKAP expression in the developing peripheral nervous system, from the onset of neural crest migration through the period of programmed cell death in the dorsal root ganglia, and (2) using RNAi, reduced expression of IKBKAP mRNA in the neural crest lineage throughout the process of dorsal root ganglia (DRG) development in chick embryos in ovo. Here we demonstrate that IKAP is not expressed by neural crest cells and instead is expressed as neurons differentiate both in the CNS and PNS, thus the devastation of the PNS in FD could not be due to disruptions in neural crest motility or migration. In addition, we show that alterations in the levels of IKAP, through both gain and loss of function studies, perturbs neuronal polarity, neuronal differentiation and survival. Thus IKAP plays pleiotropic roles in both the peripheral and central nervous systems.

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          Most cited references52

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          Elongator controls the migration and differentiation of cortical neurons through acetylation of alpha-tubulin.

          The generation of cortical projection neurons relies on the coordination of radial migration with branching. Here, we report that the multisubunit histone acetyltransferase Elongator complex, which contributes to transcript elongation, also regulates the maturation of projection neurons. Indeed, silencing of its scaffold (Elp1) or catalytic subunit (Elp3) cell-autonomously delays the migration and impairs the branching of projection neurons. Strikingly, neurons defective in Elongator show reduced levels of acetylated alpha-tubulin. Reduction of alpha-tubulin acetylation via expression of a nonacetylatable alpha-tubulin mutant leads to comparable defects in cortical neurons and suggests that alpha-tubulin is a target of Elp3. This is further supported by the demonstration that Elp3 promotes acetylation and counteracts HDAC6-mediated deacetylation of this substrate in vitro. Our results uncover alpha-tubulin as a target of the Elongator complex and suggest that a tight regulation of its acetylation underlies the maturation of cortical projection neurons.
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            Tubulin modifications and their cellular functions.

            All microtubules are built from a basic alpha/beta-tubulin building block, yet subpopulations of microtubules can be differentially marked by a number of post-translational modifications. These modifications, conserved throughout evolution, are thought to act individually or in combination to control specific microtubule-based functions, analogous to how histone modifications regulate chromatin functions. Here we review recent studies demonstrating that tubulin modifications influence microtubule-associated proteins such as severing proteins, plus-end tracking proteins, and molecular motors. In this way, tubulin modifications play an important role in regulating microtubule properties, such as stability and structure, as well as microtubule-based functions, such as ciliary beating, cell division, and intracellular trafficking.
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              Elongator, a multisubunit component of a novel RNA polymerase II holoenzyme for transcriptional elongation.

              The form of RNA polymerase II (RNAPII) engaged in transcriptional elongation was isolated. Elongating RNAPII was associated with a novel multisubunit complex, termed elongator, whose stable interaction was dependent on a hyperphosphorylated state of the RNAPII carboxy-terminal domain (CTD). A free form of elongator was also isolated, demonstrating the discrete nature of the complex, and free elongator could bind directly to RNAPII. The gene encoding the largest subunit of elongator, ELP1, was cloned. Phenotypes of yeast elp1 delta cells demonstrated an involvement of elongator in transcriptional elongation as well as activation in vivo. Our data indicate that the transition from transcriptional initiation to elongation involves an exchange of the multiprotein mediator complex for elongator in a reaction coupled to CTD hyperphosphorylation.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2012
                23 February 2012
                : 7
                : 2
                : e32050
                Affiliations
                [1]Department of Cell Biology and Neuroscience, Montana State University, Bozeman, Montana
                University of Cincinnatti, United States of America
                Author notes

                Conceived and designed the experiments: FL. Performed the experiments: BJH LG MC FL. Analyzed the data: BJH LG MC FL. Contributed reagents/materials/analysis tools: BJH LG MC. Wrote the paper: FL.

                Article
                PONE-D-11-15404
                10.1371/journal.pone.0032050
                3285659
                22384137
                61fd5ff2-60c0-4fa6-9bc3-c155d2237457
                Hunnicutt et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 4 August 2011
                : 20 January 2012
                Page count
                Pages: 11
                Categories
                Research Article
                Biology
                Anatomy and Physiology
                Biochemistry
                Neurochemistry
                Computational Biology
                Computational Neuroscience
                Developmental Biology
                Molecular Cell Biology
                Cellular Types
                Signal Transduction
                Signaling in Selected Disciplines
                Neuroscience
                Cellular Neuroscience
                Developmental Neuroscience
                Medicine
                Diagnostic Medicine
                Pathology
                Anatomical Pathology
                Neurology

                Uncategorized
                Uncategorized

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