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

7 Scopus citations

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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