During the development of central nervous system, formation of the six-layered structure of cerebral cortex is a tightly regulated process which is essential for the establishment of proper neuronal circuits and brain functions. Neuronal migration is a critical step in the development of cerebral cortex, which is highly dependent on the dynamic microtubule cytoskeleton.
Recent studies are providing more insights into the importance of tubulin post-translational modifications (PTMs) in cortical development. Previous studies reveal that impairment of α-tubulin acetylation at lysine 40 (α-TubK40ac) by knocking down the acetyltransferase MEC-17 causes migratory defects in the cortical projection neurons and interneurons, and perturbs the multipolar-to-unipolar/bipolar transition of projection neurons in the IZ region (Li et al, J Neurosci, 2012). Loss of α-tubulin acetylation also results in axon overgrowth and overbranching (Wei et al, Cereb Cortex, 2017).
A recent study reports that α-tubulin could be tri-methylated (α-TubK40me3) by SET domain containing 2 (SETD2) at the same residue undergoing acetylation (Park et al, Cell, 2016). However, the functions and mechanisms of α-TubK40me3 in microtubule properties and post-mitotic neurons are largely unclear. This work entitled “α-TubK40me3 is required for neuronal polarization and migration by promoting microtubule formation” was published online in Nature Communications on July 5, 2021. XIE Xuan, WANG Shaogang and colleagues, under the supervision of Prof. BAO Lan and Dr. FENG Wenfeng at the Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, found that α-TubK40me3 could promote microtubule formation and regulates neuronal polarization and migration.
In this study, using a specific homemade antibody against α-TubK40me3, researchers show that α-TubK40me3 is enriched in neuronal progenitor cells (NPCs) and neurons from embryonic day 14 (E14) to E16 in cerebral cortex. In utero knockdown of SETD2 at E14 leads to impaired morphological transition and thereby the migration of cortical neurons, which could be restored by overexpressing NES-SETD2(1469-1724), a cytoplasm-localized SETD2 truncation retaining enzyme activity or α-tubulinK40F, a tri-methylation mimicking mutant of α-tubulin. Mechanistically, α-TubK40me3 is preferably distributed on polymerized microtubules in cells and regulates neuronal polarization by promoting tubulin nucleation and microtubule formation. Interestingly, the duration of high-level α-TubK40me3 in the developing cerebral cortex is extended in MEC-17 knockout mice, and the impaired polarization and migration of α-TubK40ac-deficient neurons could be largely restored by overexpressing NES-SETD2(1469-1724) and α-tubulinK40F, implying a compensatory effect of α-TubK40me3. These findings greatly expand our knowledge about the functions and mechanisms of α-tubulin methylation in post-mitotic neurons.
This work was collaborated with Prof. ZHANG Xu and Prof. ZOU Weiguo. This work was funded by National Natural Science Foundation of China, the Strategic Priority Research Program of the Chinese Academy of Sciences, and the Shanghai Science and Technology Committee.
α-TubK40me3 is required for neuronal polarization and migration by promoting microtubule formation