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Impaired Function of HDAC6 Slows Down Axonal Growth and Interferes with Axon Initial Segment Development

The development of morphological neuronal polarity starts by the formation and elongation of an axon. At the same time the axon initial segment (AIS) is generated and creates a diffusion barrier which differentiate axon and somatodendritic compartment. Different structural and functional proteins th...

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Autores principales: Tapia, Mónica, Wandosell, Francisco, Garrido, Juan José
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2944822/
https://www.ncbi.nlm.nih.gov/pubmed/20886111
http://dx.doi.org/10.1371/journal.pone.0012908
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author Tapia, Mónica
Wandosell, Francisco
Garrido, Juan José
author_facet Tapia, Mónica
Wandosell, Francisco
Garrido, Juan José
author_sort Tapia, Mónica
collection PubMed
description The development of morphological neuronal polarity starts by the formation and elongation of an axon. At the same time the axon initial segment (AIS) is generated and creates a diffusion barrier which differentiate axon and somatodendritic compartment. Different structural and functional proteins that contribute to the generation of neuronal action potential are concentrated at the axon initial segment. While axonal elongation is controlled by signalling pathways that regulate cytoskeleton through microtubule associated proteins and tubulin modifications, the microtubule cytoskeleton under the AIS is mostly unknown. Thus, understanding which proteins modify tubulin, where in the neuron and at which developmental stage is crucial to understanding how morphological and functional neuronal polarity is achieved. In this study performed in mice and using a well established model of murine cultured hippocampal neurons, we report that the tubulin deacetylase HDAC6 is localized at the distal region of the axon, and its inhibition with TSA or tubacin slows down axonal growth. Suppression of HDAC6 expression with HDAC6 shRNAs or expression of a non-active mutant of HDAC6 also reduces axonal length. Furthermore, HDAC6 inhibition or suppression avoids the concentration of ankyrinG and sodium channels at the axon initial segment (AIS). Moreover, treatment of mouse cultured hippocampal neurons with detergents to eliminate the soluble pool of microtubules identified a pool of detergent resistant acetylated microtubules at the AIS, not present at the rest of the axon. Inhibition or suppression of HDAC6 increases acetylation all along the axon and disrupts the specificity of AIS cytoskeleton, modifying the axonal distal gradient localization of KIF5C to a somatodendritic and axonal localization. In conclusion, our results reveal a new role of HDAC6 tubulin deacetylase as a regulator of microtubule characteristics in the axon distal region where axonal elongation takes place, and allowing the development of acetylated microtubules microdomains where HDAC6 is not concentrated, such as the axon initial segment.
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spelling pubmed-29448222010-09-30 Impaired Function of HDAC6 Slows Down Axonal Growth and Interferes with Axon Initial Segment Development Tapia, Mónica Wandosell, Francisco Garrido, Juan José PLoS One Research Article The development of morphological neuronal polarity starts by the formation and elongation of an axon. At the same time the axon initial segment (AIS) is generated and creates a diffusion barrier which differentiate axon and somatodendritic compartment. Different structural and functional proteins that contribute to the generation of neuronal action potential are concentrated at the axon initial segment. While axonal elongation is controlled by signalling pathways that regulate cytoskeleton through microtubule associated proteins and tubulin modifications, the microtubule cytoskeleton under the AIS is mostly unknown. Thus, understanding which proteins modify tubulin, where in the neuron and at which developmental stage is crucial to understanding how morphological and functional neuronal polarity is achieved. In this study performed in mice and using a well established model of murine cultured hippocampal neurons, we report that the tubulin deacetylase HDAC6 is localized at the distal region of the axon, and its inhibition with TSA or tubacin slows down axonal growth. Suppression of HDAC6 expression with HDAC6 shRNAs or expression of a non-active mutant of HDAC6 also reduces axonal length. Furthermore, HDAC6 inhibition or suppression avoids the concentration of ankyrinG and sodium channels at the axon initial segment (AIS). Moreover, treatment of mouse cultured hippocampal neurons with detergents to eliminate the soluble pool of microtubules identified a pool of detergent resistant acetylated microtubules at the AIS, not present at the rest of the axon. Inhibition or suppression of HDAC6 increases acetylation all along the axon and disrupts the specificity of AIS cytoskeleton, modifying the axonal distal gradient localization of KIF5C to a somatodendritic and axonal localization. In conclusion, our results reveal a new role of HDAC6 tubulin deacetylase as a regulator of microtubule characteristics in the axon distal region where axonal elongation takes place, and allowing the development of acetylated microtubules microdomains where HDAC6 is not concentrated, such as the axon initial segment. Public Library of Science 2010-09-23 /pmc/articles/PMC2944822/ /pubmed/20886111 http://dx.doi.org/10.1371/journal.pone.0012908 Text en Tapia et al. http://creativecommons.org/licenses/by/4.0/ 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 properly credited.
spellingShingle Research Article
Tapia, Mónica
Wandosell, Francisco
Garrido, Juan José
Impaired Function of HDAC6 Slows Down Axonal Growth and Interferes with Axon Initial Segment Development
title Impaired Function of HDAC6 Slows Down Axonal Growth and Interferes with Axon Initial Segment Development
title_full Impaired Function of HDAC6 Slows Down Axonal Growth and Interferes with Axon Initial Segment Development
title_fullStr Impaired Function of HDAC6 Slows Down Axonal Growth and Interferes with Axon Initial Segment Development
title_full_unstemmed Impaired Function of HDAC6 Slows Down Axonal Growth and Interferes with Axon Initial Segment Development
title_short Impaired Function of HDAC6 Slows Down Axonal Growth and Interferes with Axon Initial Segment Development
title_sort impaired function of hdac6 slows down axonal growth and interferes with axon initial segment development
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2944822/
https://www.ncbi.nlm.nih.gov/pubmed/20886111
http://dx.doi.org/10.1371/journal.pone.0012908
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