期刊
CYTOSKELETON
卷 77, 期 3-4, 页码 40-54出版社
WILEY
DOI: 10.1002/cm.21567
关键词
brain development; microtubule network; neuronal cytoskeleton; TUBA1A; tubulinopathy
类别
资金
- NIGMS NIH HHS [R01 GM112893] Funding Source: Medline
The neuronal cytoskeleton performs incredible feats during nervous system development. Extension of neuronal processes, migration, and synapse formation rely on the proper regulation of microtubules. Mutations that disrupt the primary alpha-tubulin expressed during brain development, TUBA1A, are associated with a spectrum of human brain malformations. One model posits that TUBA1A mutations lead to a reduction in tubulin subunits available for microtubule polymerization, which represents a haploinsufficiency mechanism. We propose an alternative model for the majority of tubulinopathy mutations, in which the mutant tubulin polymerizes into the microtubule lattice to dominantly poison microtubule function. Nine distinct alpha-tubulin and ten beta-tubulin genes have been identified in the human genome. These genes encode similar tubulin proteins, called isotypes. Multiple tubulin isotypes may partially compensate for heterozygous deletion of a tubulin gene, but may not overcome the disruption caused by missense mutations that dominantly alter microtubule function. Here, we describe disorders attributed to haploinsufficiency versus dominant negative mechanisms to demonstrate the hallmark features of each disorder. We summarize literature on mouse models that represent both knockout and point mutants in tubulin genes, with an emphasis on how these mutations might provide insight into the nature of tubulinopathy patient mutations. Finally, we present data from a panel of TUBA1A tubulinopathy mutations generated in yeast alpha-tubulin that demonstrate that alpha-tubulin mutants can incorporate into the microtubule network and support viability of yeast growth. This perspective on tubulinopathy mutations draws on previous studies and additional data to provide a fresh perspective on how TUBA1A mutations disrupt neurodevelopment.
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