α-TubK40me3 is required for neuronal polarization and migration by promoting microtubule formation

Tri-methylation on lysine 40 of alpha -tubulin (alpha -TubK40me3) is a recently identified post-translational modification involved in mitosis and cytokinesis. However, knowledge about alpha -TubK40me3 in microtubule function and post-mitotic cells remains largely incomplete. Here, we report that alpha -TubK40me3 is required for neuronal polarization and migration by promoting microtubule formation. alpha -TubK40me3 is enriched in mouse cerebral cortex during embryonic day (E)14 to E16. Knockdown of alpha -tubulin methyltransferase SETD2 at E14 leads to the defects in neuronal migration, which could be restored by overexpressing either a cytoplasm-localized SETD2 truncation or alpha -TubK40me3-mimicking mutant. Furthermore, alpha -TubK40me3 is preferably distributed on polymerized microtubules and potently promotes tubulin nucleation. Downregulation of alpha -TubK40me3 results in reduced microtubule abundance in neurites and disrupts neuronal polarization, which could be rescued by Taxol. Additionally, alpha -TubK40me3 is increased after losing alpha -tubulin K40 acetylation (alpha -TubK40ac) and largely rescues alpha -TubK40ac function. This study reveals a critical role of alpha -TubK40me3 in microtubule formation and neuronal development. Post-translational modifications of tubulins regulate microtubule properties and neural development. Here, the authors report that one such post-translational modification, alpha -TubK40me3, is required for neuronal polarization and migration by promoting microtubule formation.

Automated summary

The post-translational modification α-TubK40me3 plays a crucial role in neuronal polarization and migration by promoting microtubule formation. This modification is enriched in the mouse cerebral cortex during embryonic development, and its deficiency leads to defects in neuronal migration that can be rescued by overexpression of specific proteins. Additionally, α-TubK40me3 potently promotes tubulin nucleation and is involved in tubulin acetylation regulation, highlighting its importance in microtubule dynamics and neuronal development.