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

Mol Biol Cell. 2017 Oct 15;28(21):2786-2801. doi: 10.1091/mbc.E17-06-0424. Epub 2017 Aug 23.


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.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Caenorhabditis elegans / growth & development*
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / chemistry
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism
  • Humans
  • Microtubules / genetics
  • Microtubules / physiology
  • Mutation
  • Neurites / metabolism*
  • Neurites / physiology*
  • Neurogenesis
  • Neurons / metabolism
  • Protein Isoforms / genetics
  • Tubulin / chemistry
  • Tubulin / genetics*
  • Tubulin / metabolism*


  • Caenorhabditis elegans Proteins
  • Protein Isoforms
  • Tubulin