%0 Journal Article %A Chaogu Zheng %A Margarete Diaz-Cuadros %A Susan Laura Jao %A Ken C.Q. Nguyen %A David H. Hall %A Martin Chalfie %T Distinct effects of tubulin isotype mutations on neurite growth in Caenorhabditis elegans %D 2017 %R 10.1101/131326 %J bioRxiv %P 131326 %X Tubulins, the building block of microtubules (MTs), play a critical role in both supporting and regulating neurite growth. Eukaryotic genomes contain multiple α and β tubulin isotypes, and their dominant missense mutations cause a wide range of neurodevelopmental defects in humans. Thus, identifying the specific functions of each tubulin isotype and evaluating how particular mutations would change those functions during neuronal morphogenesis is fundamental for understanding MT functions in the nervous system. Using the C. elegans touch receptor neurons (TRNs), we analyzed the effects of 67 missense mutations in the mec-12/α-tubulin and mec-7/β-tubulin genes on neurite growth. Three types of mutations emerged: 1) loss-of-function mutations, which are found throughout the molecule and cause mild defects in neurite growth; 2) antimorphic mutations, which map to the GTP binding site and intradimer and interdimer interaction interfaces and significantly reduced MT stability, causing severe defects in the growth of all TRN neurites; and 3) neomorphic mutations, which map to the exterior surface and increased MT stability, causing ectopic neurite growth. Such structure-function analysis revealed a causal relationship between tubulin structure and interactions and MT stability, which in turn affects neuronal morphogenesis. Importantly, we engineered several disease-associated human tubulin mutations into C. elegans genes and examine their impact on neuronal development at cellular level. We also discovered a MT-destabilizing α-tubulin isotype TBA-7, whose loss 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. %U https://www.biorxiv.org/content/biorxiv/early/2017/06/18/131326.full.pdf