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. 2017 Sep;5(3):8.
doi: 10.3390/jdb5030008. Epub 2017 Sep 19.

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

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Free PMC article

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

Jayne Aiken et al. J Dev Biol. .
Free PMC article

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.

Keywords: TUBA1A; lissencephaly; microtubule; neurodevelopment; polymicrogyria; tubulinopathy.

Conflict of interest statement

Conflicts of Interest: The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Microtubule structure and dynamics. (A) Heterodimer conformation in GTP and GDP states; (B) lattice conformation with labeled longitudinal and lateral interfaces; and (C) Microtubule conformation during polymerization and depolymerization.
Figure 2
Figure 2
Overview of microtubule tasks during neuron maturation: (A) During neurite initiation, microtubules invade nascent lamellipodium; (B) microtubules form bundles to stabilize neurites; (C) microtubules form a perinuclear cage and provide force for nucleokinesis during neuronal migration; (D) in the migrating growth cone, microtubules stabilize and aid leading process growth; (E) polarized, bundled microtubules provide structural backbone of axon; (F) microtubules act as a transportation track for microtubule motors; (G) microtubules support axonal growth cone dynamics; and (H) microtubules of mixed polarity provide support to dendrites.
Figure 3
Figure 3
Potential consequences of TUBA1A mutations. TUBA1A mutations may lead to (A) protein folding defects or heterodimer instability; or (B) altered lattice interactions. Either of these defects may produce haploinsufficiency/loss of function consequences, resulting in fewer polymerization competent tubulin heterodimers available to form microtubules, or changes in microtubule dynamics. This also may lead to changes in the ratio of α-tubulin isotypes present in the microtubule lattice; (C) TUBA1A mutations may lead to mutant tubulin heterodimers that appropriately polymerize and cause toxic, gain of function consequences from within the microtubule lattice. Once in the lattice, mutant dimers may intrinsically change microtubule behavior or extrinsically alter MAP binding.
Figure 4
Figure 4
Dataset of RNA-Seq results for α-tubulin isotypes in mouse nervous system cell population. Distribution of α-tubulin isotype mRNA expression in various cell types generated from P7-17 mouse cerebral cortex. OPC population contains 5% microglial contamination. Adapted from [141].
Figure 5
Figure 5
Transcriptional regulation of TUBA1A in mouse cortical progenitors. (A) FGF/PDGF treatment of cortical progenitors leads to a phosphorylation cascade activating MEK/ERK, Rsk, and C/EBP; and (B) in the nucleus, phosphorylated C/EBP directly binds three conserved C/EBP binding sites in the TUBA1A promoter, leading to transcription of TUBA1A and neurogenesis. Based on data from [153].

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