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

Jayne Aiken,Jeffrey K. Moore,Georgia Buscaglia,Emily A. Bates

doi:10.3390/jdb5030008

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.

Highlights

Brain development is a highly complex process that requires careful coordination of cell proliferation, differentiation, migration, axon and dendrite growth and guidance, and synapse formation
The α-tubulin gene TUBA1A has emerged as a vital component in the development of the nervous system
With the identification of tubulinopathy-causing TUBA1A mutations, understanding how TUBA1A must function during neural development becomes an urgent inquiry

Summary

Introduction

Brain development is a highly complex process that requires careful coordination of cell proliferation, differentiation, migration, axon and dendrite growth and guidance, and synapse formation. Each of these cellular tasks rely on the proper regulation of microtubules, which are dynamic cytoskeletal polymers that help provide structure and generate force in all eukaryotic cell types. Exploring how TUBA1A contributes to neuronal function will provide important insight into how cells “tune” their microtubule networks using the programmed expression of a specific tubulin isotype. We will focus on TUBA1A, discussing its regulated expression, mutations associated with brain malformations, and how this α-tubulin might uniquely contribute to normal brain development

Microtubule Basics

Tubulin Isotypes

Tubulin Post-Translational Modifications

Roles of Microtubules during Neuronal Development and Adulthood

Potential

TUBA1A Mutations Linked to Lissencephaly

TUBA1A Mutations Linked to Polymicrogyria

TUBA1A Mutations Linked to Microcephaly

TUBA1A Mutations Linked to Cerebellar Dysplasia

Summary of TUBA1A Mutations Associated with Brain Malformations

Cellular Impact of TUBA1A Mutations

TUBA1A Expression Pattern