The α-Tubulin gene TUBA1A in Brain Development: A Key Ingredient in the Neuronal Isotype Blend

Abstract

Microtubules are dynamic cytoskeletal polymers that mediate numerous, essential functions such as axon and dendrite growth and neuron migration throughout brain development. In recent years, sequencing has revealed dominant mutations that disrupt the tubulin protein building blocks of microtubules. These tubulin mutations lead to a spectrum of devastating brain malformations, complex neurological and physical phenotypes, and even fatality. The most common tubulin gene mutated is the α-tubulin gene TUBA1A, which is the most prevalent α-tubulin gene expressed in post-mitotic neurons. The normal role of TUBA1A during neuronal maturation, and how mutations alter its function to produce the phenotypes observed in patients, remains unclear. This review synthesizes current knowledge of TUBA1A function and expression during brain development, and the brain malformations caused by mutations in TUBA1A.

UniPath: A uniform approach for pathway and gene-set based analysis of heterogeneity in single-cell epigenome and transcriptome profiles

“…6b). These genes are involved in the differentiation of oligodendrocyte-precursor towards mature oligodendrocytes [38][39][40][41]. On the same trend, we found two new clusters of "unknown" cells from the bladder in MCA data-set ( Fig.…”

Tubulin mutations in brain development disorders: Why haploinsufficiency does not explain TUBA1A tubulinopathies

“…Tubulin isotypes have divergent expression profiles, with unique blends of isotypes expressed in different cell types. In developing mammalian neurons, TUBA1A is the primary α‐tubulin isotype, representing approximately 95% of α‐tubulin mRNA during brain development (Figure ; Lewis, Lee, & Cowan, ; Miller, Naus, Durand, Bloom, & Milner, ; Zhang et al, ; reviewed in Aiken, Buscaglia, Bates, & Moore, ). During later stages, the expression of TUBA1A declines (Lewis et al, ).…”

TUBA1A mutations identified in lissencephaly patients dominantly disrupt neuronal migration and impair dynein activity

“…In principle, mutations to TUBA1A could alter α-tubulin function at the levels of: 1) tubulin heterodimer formation ( Figure 3A), 2) tubulin heterodimer polymerization to form microtubules ( Figure 3B), or 3) MAP binding to polymerized microtubules ( Figure 3C), or a combination of these effects (Aiken et al 2017). To isolate the functional consequences of TUBA1A-R402C and R402H substitutions on a molecular level, we made analogous mutations in budding yeast α-tubulin.…”

“…Interestingly, patients with different TUBA1A mutations exhibit a wide spectrum of brain malformations (Keays et al 2007;Poirier et al 2007;Bahi-Buisson et al 2008;Fallet-Bianco et al 2008;Morris-Rosendahl et al 2008;Kumar et al 2010;Lecourtois et al 2010;Poirier et al 2013;Cushion et al 2013;Bahi-Buisson et al 2014). The variability of mutations and phenotypes underscores the possibility that different mutations may cause distinct defects in microtubule function, ultimately impacting brain development in drastically different ways (Bahi-Buisson et al 2014;Aiken et al 2017). However, we have little evidence of the molecular consequences of tubulin mutations, or how molecular changes to the microtubule network may give rise to the observed brain phenotypes.…”

“…In addition, yeast maintain many of the homologous microtubule associated proteins present in mammalian cells. Using yeast to investigate the functional consequences of mutations identified in tubulinopathy patients provides an opportunity to determine how a substitution alters tubulin function: 1) does the mutant α-tubulin form functional tubulin heterodimers, 2) can mutant heterodimers polymerize into microtubules, and/or 3) do mutant heterodimers alter binding of conserved microtubule associate proteins (MAPs) to the microtubule network (Aiken et al 2017).…”