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

Chaogu Zheng, Margarete Diaz-Cuadros, Ken C.Q. Nguyen, David H. Hall, Martin Chalfie

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2786-2801
Number of pages16
JournalMolecular Biology of the Cell
Volume28
Issue number21
DOIs
StatePublished - Oct 15 2017

Fingerprint

Caenorhabditis elegans
Neurites
Tubulin
Microtubules
Mutation
Growth
Missense Mutation
Touch
Guanosine Triphosphate
Morphogenesis
Binding Sites
Genome
Neurons
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

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.

In: Molecular Biology of the Cell, Vol. 28, No. 21, 15.10.2017, p. 2786-2801.

Research output: Contribution to journalArticle

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. In: Molecular Biology of the Cell. 2017 ; Vol. 28, No. 21. pp. 2786-2801.
@article{8f7c6a4907744f90b640bd00164557db,
title = "Distinct effects of tubulin isotype mutations on neurite growth in Caenorhabditis elegans",
abstract = "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.",
author = "Chaogu Zheng and Margarete Diaz-Cuadros and Nguyen, {Ken C.Q.} and Hall, {David H.} and Martin Chalfie",
year = "2017",
month = "10",
day = "15",
doi = "10.1091/mbc.E17-06-0424",
language = "English (US)",
volume = "28",
pages = "2786--2801",
journal = "Molecular Biology of the Cell",
issn = "1059-1524",
publisher = "American Society for Cell Biology",
number = "21",

}

TY - JOUR

T1 - Distinct effects of tubulin isotype mutations on neurite growth in Caenorhabditis elegans

AU - Zheng, Chaogu

AU - Diaz-Cuadros, Margarete

AU - Nguyen, Ken C.Q.

AU - Hall, David H.

AU - Chalfie, Martin

PY - 2017/10/15

Y1 - 2017/10/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85031280281&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85031280281&partnerID=8YFLogxK

U2 - 10.1091/mbc.E17-06-0424

DO - 10.1091/mbc.E17-06-0424

M3 - Article

C2 - 28835377

AN - SCOPUS:85031280281

VL - 28

SP - 2786

EP - 2801

JO - Molecular Biology of the Cell

JF - Molecular Biology of the Cell

SN - 1059-1524

IS - 21

ER -