MEC-17 Deficiency Leads to Reduced α-Tubulin Acetylation and Impaired Migration of Cortical Neurons

Abstract

Neuronal migration is a fundamental process during the development of the cerebral cortex and is regulated by cytoskeletal components. Microtubule dynamics can be modulated by posttranslational modifications to tubulin subunits. Acetylation of ␣-tubulin at lysine 40 is important in regulating microtubule properties, and this process is controlled by acetyltransferase and deacetylase. MEC-17 is a newly discovered ␣-tubulin acetyltransferase that has been found to play a major role in the acetylation of ␣-tubulin in different species in vivo. However, the physiological function of MEC-17 during neural development is largely unknown. Here, we report that MEC-17 is critical for the migration of cortical neurons in the rat. MEC-17 was strongly expressed in the cerebral cortex during development. MEC-17 deficiency caused migratory defects in the cortical projection neurons and interneurons, and perturbed the transition of projection neurons from the multipolar stage to the unipolar/bipolar stage in the intermediate zone of the cortex. Furthermore, knockdown of ␣-tubulin deacetylase HDAC6 or overexpression of tubulin K40Q to mimic acetylated ␣-tubulin could reduce the migratory and morphological defects caused by MEC-17 deficiency in cortical projection neurons. Thus, MEC-17, which regulates the acetylation of ␣-tubulin, appears to control the migration and morphological transition of cortical neurons. This finding reveals the importance of MEC-17 and ␣-tubulin acetylation in cortical development.

Molecular basis of the acetyltransferase activity of MEC-17 towards α-tubulin

“…Four days later, the positions of cells in the cortical wall of the developing somatosensory cortex were examined. Consistent with our previous report [1], at postnatal day 0 (P0), 47% of the neurons expressing the control shRNA (Ctrl shRNA) migrated to the cortical plate (CP) and only 53% remained in the intermediate zone (IZ) and ventricular/subventricular zones (VZ/SVZ) ( Figure 1F). In contrast, 97% of the MEC-17-deficient neurons remained in IZ and VZ/SVZ ( Figure 1F).…”

“…In particular, acetylation of α-tubulin affects the cell motility and plays an important role in neuronal migration and differentiation [1]. Specifically, acetylation of Lys40 of α-tubulin has prominent impacts on polarized protein trafficking and hence protein transport by promoting the binding of dynein/dynactin and kinesin-1 motor complexes [2,3].…”

“…MEC-17 is highly expressed in the cerebral cortex during development and MEC-17 deficiency leads to impaired migration of cortical neurons [1]. To examine whether the acetyltransferase activity of MEC-17 is required for radial migration of cortical projection neurons during development, the rats at embryo day 16.5 (E16.5) were electroporated with GFP-expressing plasmid and indicated plasmids expressing MEC-17 shRNAs ( Figure 1F).…”

Epothilone B Benefits Nigrostriatal Pathway Recovery by Promoting Microtubule Stabilization After Intracerebral Hemorrhage

“…Furthermore, this study also revealed that the loss of MEC‐17 (αTAT1) expression leads to microtubule instability, axonal degeneration, and disrupted axonal transport in Caenorhabditis elegans 37. In addition, MEC‐17 (αTAT1) deficiency leads to reduced α‐tubulin acetylation and impaired migration of cortical neurons in mice 38. We found that αTAT1 knockdown by shRNA decreased the expression of acetylated α‐tubulin in vivo and in vitro, which is consistent with the findings observed in C. elegans 37.…”

Roles of intracellular fibroblast growth factors in neural development and functions

“…During brain development, cortical neurons migrate from the site of their last mitotic division towards their final destination and generate the proper neural circuits [46][47][48]. Proper regulation of microtubule dynamics during axon/leading process formation is crucial for the transition of neurons from the multipolar stage to a bipolar morphology, and is a prerequisite for initiating radial migration [49][50][51]. Tubulins, a number of microtubule-regulating proteins that promote microtubule assembly and proteins that protect microtubules from depolymerization (such as microtubulestabilizing proteins), are all involved in this regulatory process [52].…”