Actin waves transport RanGTP to the neurite tip to regulate non-centrosomal microtubules in neurons

Abstract

Microtubule (MT) is the most abundant cytoskeleton in neurons and controls multiple facets of their development. While the MT-organizing center (MTOC) in mitotic cells is typically located at the centrosome, MTOC in neurons switches to non-centrosomal sites. A handful of cellular components have been shown to promote non-centrosomal MT (ncMT) formation in neurons, yet the regulation mechanism remains unknown. Here we demonstrate that the small GTPase Ran is a key regulator of ncMTs in neurons. Using an optogenetic tool that enables light-induced local production of RanGTP, we demonstrate that RanGTP promotes ncMT plus-end growth along the neurite. Additionally, we discovered that actin waves drive the anterograde transport of RanGTP. Pharmacological disruption of actin waves abolishes the enrichment of RanGTP and reduces growing ncMT plus-ends at the neurite tip. These observations identify a novel regulation mechanism of ncMTs and pinpoint an indirect connection between the actin and MT cytoskeletons in neurons.

B-type plexins regulate mitosis via RanGTPase

“…Cells expressing either constitutively active RanQ69L or the dominant-negative RanT24N give rise to abnormal spindles, showing that the correct balance between RanGTP/GDP is essential for proper spindle formation. 38…”

With the Permission of Microtubules: An Updated Overview on Microtubule Function During Axon Pathfinding

“…The γTuRC-dependent MT nucleation in eukaryotic cells undergoes spatial and temporal regulation by means of additional MAPs, such as TPX2 and its activator RanGTP, and both proteins have been found to be enriched at neuritic tips ( Chen et al, 2017 ; Huang et al, 2020 ; Liu et al, 2021 ). MT-bound TPX2 participates in MT nucleation at elongating neurite tips in cultured hippocampal neurons ( Chen et al, 2017 ).…”

“…MT-bound TPX2 participates in MT nucleation at elongating neurite tips in cultured hippocampal neurons ( Chen et al, 2017 ). RanGTP is transported anterogradely along the axons through actin waves, it colocalizes with actin-based structures in the axonal GC and enables local nucleation events at neurite tips ( Chen et al, 2017 ; Huang et al, 2020 ). Actin waves (also known as growth cone-like waves) are dynamic cytoskeletal structures traveling anterogradely along the axon shaft.…”

Distinct Microtubule Organizing Center Mechanisms Combine to Generate Neuron Polarity and Arbor Complexity

“…In cultured rodent hippocampal neurons, a local increase in microtubule generation activity occurs in the wake of the wave (Winans et al, 2016; Figure 1B). It is possible that RanGTP-Tpx2 based mechanisms are responsible for this local amplification of microtubule generation as actin waves transport RanGTP (Huang et al, 2020; Figure 1B).…”