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Distinct effects of tubulin isotype mutations on neurite growth in Caenorhabditis elegans

Tubulins, the building block of microtubules (MTs), play a critical role in both supporting and regulating neurite growth. Eukaryotic genomes contain multiple tubulin isotypes, and their missense mutations cause a range of neurodevelopmental defects. Using the Caenorhabditis elegans touch receptor n...

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Autores principales: Zheng, Chaogu, Diaz-Cuadros, Margarete, Nguyen, Ken C. Q., Hall, David H., Chalfie, Martin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5638583/
https://www.ncbi.nlm.nih.gov/pubmed/28835377
http://dx.doi.org/10.1091/mbc.E17-06-0424
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author Zheng, Chaogu
Diaz-Cuadros, Margarete
Nguyen, Ken C. Q.
Hall, David H.
Chalfie, Martin
author_facet Zheng, Chaogu
Diaz-Cuadros, Margarete
Nguyen, Ken C. Q.
Hall, David H.
Chalfie, Martin
author_sort Zheng, Chaogu
collection PubMed
description Tubulins, the building block of microtubules (MTs), play a critical role in both supporting and regulating neurite growth. Eukaryotic genomes contain multiple tubulin isotypes, and their missense mutations cause a range of neurodevelopmental defects. Using the Caenorhabditis elegans touch receptor neurons, we analyzed the effects of 67 tubulin missense mutations on neurite growth. Three types of mutations emerged: 1) loss-of-function mutations, which cause mild defects in neurite growth; 2) antimorphic mutations, which map to the GTP binding site and intradimer and interdimer interfaces, significantly reduce MT stability, and cause severe neurite growth defects; and 3) neomorphic mutations, which map to the exterior surface, increase MT stability, and cause ectopic neurite growth. Structure-function analysis reveals a causal relationship between tubulin structure and MT stability. This stability affects neuronal morphogenesis. As part of this analysis, we engineered several disease-associated human tubulin mutations into C. elegans genes and examined their impact on neuronal development at the cellular level. We also discovered an α-tubulin (TBA-7) that appears to destabilize MTs. Loss of TBA-7 led to the formation of hyperstable MTs and the generation of ectopic neurites; the lack of potential sites for polyamination and polyglutamination on TBA-7 may be responsible for this destabilization.
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spelling pubmed-56385832017-12-30 Distinct effects of tubulin isotype mutations on neurite growth in Caenorhabditis elegans Zheng, Chaogu Diaz-Cuadros, Margarete Nguyen, Ken C. Q. Hall, David H. Chalfie, Martin Mol Biol Cell Articles Tubulins, the building block of microtubules (MTs), play a critical role in both supporting and regulating neurite growth. Eukaryotic genomes contain multiple tubulin isotypes, and their missense mutations cause a range of neurodevelopmental defects. Using the Caenorhabditis elegans touch receptor neurons, we analyzed the effects of 67 tubulin missense mutations on neurite growth. Three types of mutations emerged: 1) loss-of-function mutations, which cause mild defects in neurite growth; 2) antimorphic mutations, which map to the GTP binding site and intradimer and interdimer interfaces, significantly reduce MT stability, and cause severe neurite growth defects; and 3) neomorphic mutations, which map to the exterior surface, increase MT stability, and cause ectopic neurite growth. Structure-function analysis reveals a causal relationship between tubulin structure and MT stability. This stability affects neuronal morphogenesis. As part of this analysis, we engineered several disease-associated human tubulin mutations into C. elegans genes and examined their impact on neuronal development at the cellular level. We also discovered an α-tubulin (TBA-7) that appears to destabilize MTs. Loss of TBA-7 led to the formation of hyperstable MTs and the generation of ectopic neurites; the lack of potential sites for polyamination and polyglutamination on TBA-7 may be responsible for this destabilization. The American Society for Cell Biology 2017-10-15 /pmc/articles/PMC5638583/ /pubmed/28835377 http://dx.doi.org/10.1091/mbc.E17-06-0424 Text en © 2017 Zheng, Diaz-Cuadros, et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology.
spellingShingle Articles
Zheng, Chaogu
Diaz-Cuadros, Margarete
Nguyen, Ken C. Q.
Hall, David H.
Chalfie, Martin
Distinct effects of tubulin isotype mutations on neurite growth in Caenorhabditis elegans
title Distinct effects of tubulin isotype mutations on neurite growth in Caenorhabditis elegans
title_full Distinct effects of tubulin isotype mutations on neurite growth in Caenorhabditis elegans
title_fullStr Distinct effects of tubulin isotype mutations on neurite growth in Caenorhabditis elegans
title_full_unstemmed Distinct effects of tubulin isotype mutations on neurite growth in Caenorhabditis elegans
title_short Distinct effects of tubulin isotype mutations on neurite growth in Caenorhabditis elegans
title_sort distinct effects of tubulin isotype mutations on neurite growth in caenorhabditis elegans
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5638583/
https://www.ncbi.nlm.nih.gov/pubmed/28835377
http://dx.doi.org/10.1091/mbc.E17-06-0424
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