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

Author:

Zheng Chaogu1,Diaz-Cuadros Margarete1,Nguyen Ken C. Q.2,Hall David H.2,Chalfie Martin1

Affiliation:

1. Department of Biological Sciences, Columbia University, New York, NY 10027

2. Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461

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.

Publisher

American Society for Cell Biology (ASCB)

Subject

Cell Biology,Molecular Biology

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