Microtubule stabilization specifies initial neuronal polarization

Abstract

Axon formation is the initial step in establishing neuronal polarity. We examine here the role of microtubule dynamics in neuronal polarization using hippocampal neurons in culture. We see increased microtubule stability along the shaft in a single neurite before axon formation and in the axon of morphologically polarized cells. Loss of polarity or formation of multiple axons after manipulation of neuronal polarity regulators, synapses of amphids defective (SAD) kinases, and glycogen synthase kinase-3β correlates with characteristic changes in microtubule turnover. Consistently, changing the microtubule dynamics is sufficient to alter neuronal polarization. Application of low doses of the microtubule-destabilizing drug nocodazole selectively reduces the formation of future dendrites. Conversely, low doses of the microtubule-stabilizing drug taxol shift polymerizing microtubules from neurite shafts to process tips and lead to the formation of multiple axons. Finally, local stabilization of microtubules using a photoactivatable analogue of taxol induces axon formation from the activated area. Thus, local microtubule stabilization in one neurite is a physiological signal specifying neuronal polarization.

Tissue-specific control of midbody microtubule stability by Citron kinase through modulation of TUBB3 phosphorylation

“…Previous results indicated that the primary function of CIT-K, conserved from insects to mammals, is to promote the stability and the maturation of midbody before abscission. 15,[23][24][25] To assess whether this function may involve the stabilization of midbody microtubules, we measured the ratio of acetylated versus tyrosinated α-tubulin at the midbody of control cells and of cells lacking CIT-K. 28 Indeed, dynamic microtubules contain a relatively high amount of α-tubulin tyrosinated at its carboxyterminus, whereas stable microtubules show a high content of α-tubulin acetylated at the K40 residue. 29 We studied two cellular models characterized by different sensitivity to CIT-K loss and by different physiological relevance: cultures of proliferating neocortical neuronal progenitors obtained from control or from Cit-K knockout mice at embryonic day (E)12.5 and HeLa cells depleted of CIT-K by RNAi.…”

HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity

“…Neuron polarization consists of morphological polarization that involve preferential elongation of the axon; sorting of proteins in different compartments; and functional polarization, in which the AIS barrier is also involved. It is a very complex phenomenon that requires local destabilization of actin 62 and local stabilization of MTs 63 . RhoA activation is known to decrease actin turnover, stabilizing actin, and thus participating in axon retraction 64 .…”

Microtubule Organization and Microtubule-Associated Proteins (MAPs)

“…It has been demonstrated that axonal MTs are more resistant to the MT depolymerizing drug nocodazole compared to the dendritic MT population (Baas et al 1991;Witte et al 2008). Recently, a new posttranslational modification of tubulin has been identified that directly confers stability to MTs (Song et al 2013).…”

“…There is a clear correlation between MT acetylation/detyrosination and stable MTs, and MT tyrosination with dynamic MTs. The different MT posttranslational modifications show a polarized distribution in neurons (Hammond et al 2010;Kollins et al 2009;Witte et al 2008). In growing axons, the ratios of acetylated and Fig.…”