Tubulins and brain development – The origins of functional specification

Abstract

The development of the vertebrate central nervous system is reliant on a complex cascade of biological processes that include mitotic division, relocation of migrating neurons, and the extension of dendritic and axonal processes. Each of these cellular events requires the diverse functional repertoire of the microtubule cytoskeleton for the generation of forces, assembly of macromolecular complexes and transport of molecules and organelles. The tubulins are a multi-gene family that encode for the constituents of microtubules, and have been implicated in a spectrum of neurological disorders. Evidence is building that different tubulins tune the functional properties of the microtubule cytoskeleton dependent on the cell type, developmental profile and subcellular localisation. Here we review of the origins of the functional specification of the tubulin gene family in the developing brain at a transcriptional, translational, and post-transcriptional level. We remind the reader that tubulins are not just loading controls for your average Western blot.

Microcephaly with a simplified gyral pattern in a child with a de novo TUBA1A variant

“…He was treated with Phenobarbitone (10 mg twice a day) and Levetiracetam The tubulins are a family of proteins that make up the constituents of microtubules, which play key roles in processes such as cell proliferation, neuronal migration, and cortical laminar organization in the developing brain. The human genome includes seven αand eight β-tubulin genes which share~88% of sequence homology (Breuss, Leca, Gstrein, Hansen, & Keays, 2017). Pathogenic variants in genes such as TUBB1 and TUBA4A cause distinct pathologies, while those in others result in overlapping phenotypes.…”

Novel PCNT variants in MOPDII with attenuated growth restriction and pachygyria

“…Unlike α‐tubulin and β‐tubulin, γ‐tubulin is not incorporated in the microtubule lattice but localizes to the centrosome during interphase. Defective microtubule function has been shown to lead to insufficient proliferation and ultimately, microcephaly 12,13 . Microtubule nucleation precedes the formation of bipolar spindles and separation of chromosomes in mitosis, steps that are necessary for the progression of the cell cycle.…”

The Mechanical Role of Microtubules in Tissue Remodeling

“…[ 15 ] For example, the beta‐tubulin isotype (βTub85D) is required for meiosis and axoneme assembly in the Drosophila male germline, [ 16 ] while the beta‐tubulin isotype βVI (TUBB1) determines the final cell shape of platelets, [ 17 ] and the beta‐tubulin isotype βIII (TUBB3) yields neural migration in mice (reviewed in ref. [18]). While the molecular mechanisms of isotype‐specific regulation of microtubule function is not fully understood, in vitro studies with purified recombinant tubulin demonstrated isotype specific polymerization dynamics.…”