Abstract
Tri-methylation on lysine 40 of α-tubulin (α-TubK40me3) is a recently identified post-translational modification involved in mitosis and cytokinesis. However, knowledge about α-TubK40me3 in microtubule function and post-mitotic cells remains largely incomplete. Here, we report that α-TubK40me3 is required for neuronal polarization and migration by promoting microtubule formation. α-TubK40me3 is enriched in mouse cerebral cortex during embryonic day (E)14 to E16. Knockdown of α-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 α-TubK40me3-mimicking mutant. Furthermore, α-TubK40me3 is preferably distributed on polymerized microtubules and potently promotes tubulin nucleation. Downregulation of α-TubK40me3 results in reduced microtubule abundance in neurites and disrupts neuronal polarization, which could be rescued by Taxol. Additionally, α-TubK40me3 is increased after losing α-tubulin K40 acetylation (α-TubK40ac) and largely rescues α-TubK40ac function. This study reveals a critical role of α-TubK40me3 in microtubule formation and neuronal development.
Highlights
Tri-methylation on lysine 40 of α-tubulin (α-TubK40me3) is a recently identified posttranslational modification involved in mitosis and cytokinesis
Projection neurons within the cerebral cortex are derived from neuronal progenitor cells (NPCs) in the ventricular zone (VZ) and subventricular zone (SVZ), and radically migrate along the basal processes of radial glial progenitors (RGPs) to their final destinations in the cortical plate (CP)[11,12]
In this study, using a specific homemade antibody against αTubK40me[3], we show that α-TubK40me[3] is enriched in NPCs and neurons from embryonic day 14 (E14) to E16 in cerebral cortex
Summary
Tri-methylation on lysine 40 of α-tubulin (α-TubK40me3) is a recently identified posttranslational modification involved in mitosis and cytokinesis. Knowledge about αTubK40me[3] in microtubule function and post-mitotic cells remains largely incomplete. We report that α-TubK40me[3] is required for neuronal polarization and migration by promoting microtubule formation. The functions of α-TubK40me[3] in microtubule formation and post-mitotic cells are largely unclear. During the development of central nervous system (CNS), 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[11]. Projection neurons within the cerebral cortex are derived from neuronal progenitor cells (NPCs) in the ventricular zone (VZ) and subventricular zone (SVZ), and radically migrate along the basal processes of radial glial progenitors (RGPs) to their final destinations in the cortical plate (CP)[11,12]. Bipolar neurons extend their leading processes to the outer surface of cerebral cortex, translocate their nucleus into the leading processes and retract the trailing processes[11,12]
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