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Ran-dependent TPX2 activation promotes acentrosomal microtubule nucleation in neurons

View Article: PubMed Central - PubMed

ABSTRACT

The microtubule (MT) cytoskeleton is essential for the formation of morphologically appropriate neurons. The existence of the acentrosomal MT organizing center in neurons has been proposed but its identity remained elusive. Here we provide evidence showing that TPX2 is an important component of this acentrosomal MT organizing center. First, neurite elongation is compromised in TPX2-depleted neurons. In addition, TPX2 localizes to the centrosome and along the neurite shaft bound to MTs. Depleting TPX2 decreases MT formation frequency specifically at the tip and the base of the neurite, and these correlate precisely with the regions where active GTP-bound Ran proteins are enriched. Furthermore, overexpressing the downstream effector of Ran, importin, compromises MT formation and neuronal morphogenesis. Finally, applying a Ran-importin signaling interfering compound phenocopies the effect of TPX2 depletion on MT dynamics. Together, these data suggest a model in which Ran-dependent TPX2 activation promotes acentrosomal MT nucleation in neurons.

No MeSH data available.


Schematic model for the Ran-activated TPX2 in microtubule nucleation.MT-bound TPX2 molecules are activated by the RanGTP gradient, which is concentrated at the tip of the neurite and in the soma.
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f8: Schematic model for the Ran-activated TPX2 in microtubule nucleation.MT-bound TPX2 molecules are activated by the RanGTP gradient, which is concentrated at the tip of the neurite and in the soma.

Mentions: In this study, we discovered that TPX2 participated in neuronal morphogenesis and localized to MTs along the neurite shaft. Depleting TPX2 in neurons causes a decrease in MT emanation frequency specifically at the distal and proximal neurite regions. Interestingly, these neurite regions overlap with the distribution of RanGTP in the neuron. Overexpressing importin-α, the downstream target of Ran, decreases MT emanation frequency inside the neurite and compromises neuronal morphogenesis. Treating neurons with a Ran-importin-β interfering compound phenocopies the effect of TPX2 depletion on MT emanation. These data suggest a model in which the spatially restricted RanGTP gradient activates the MT-bound TPX2 and promotes MT nucleation in the soma (potentially from the centrosome) as well as in the distal neurite (Fig. 8).


Ran-dependent TPX2 activation promotes acentrosomal microtubule nucleation in neurons
Schematic model for the Ran-activated TPX2 in microtubule nucleation.MT-bound TPX2 molecules are activated by the RanGTP gradient, which is concentrated at the tip of the neurite and in the soma.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5304320&req=5

f8: Schematic model for the Ran-activated TPX2 in microtubule nucleation.MT-bound TPX2 molecules are activated by the RanGTP gradient, which is concentrated at the tip of the neurite and in the soma.
Mentions: In this study, we discovered that TPX2 participated in neuronal morphogenesis and localized to MTs along the neurite shaft. Depleting TPX2 in neurons causes a decrease in MT emanation frequency specifically at the distal and proximal neurite regions. Interestingly, these neurite regions overlap with the distribution of RanGTP in the neuron. Overexpressing importin-α, the downstream target of Ran, decreases MT emanation frequency inside the neurite and compromises neuronal morphogenesis. Treating neurons with a Ran-importin-β interfering compound phenocopies the effect of TPX2 depletion on MT emanation. These data suggest a model in which the spatially restricted RanGTP gradient activates the MT-bound TPX2 and promotes MT nucleation in the soma (potentially from the centrosome) as well as in the distal neurite (Fig. 8).

View Article: PubMed Central - PubMed

ABSTRACT

The microtubule (MT) cytoskeleton is essential for the formation of morphologically appropriate neurons. The existence of the acentrosomal MT organizing center in neurons has been proposed but its identity remained elusive. Here we provide evidence showing that TPX2 is an important component of this acentrosomal MT organizing center. First, neurite elongation is compromised in TPX2-depleted neurons. In addition, TPX2 localizes to the centrosome and along the neurite shaft bound to MTs. Depleting TPX2 decreases MT formation frequency specifically at the tip and the base of the neurite, and these correlate precisely with the regions where active GTP-bound Ran proteins are enriched. Furthermore, overexpressing the downstream effector of Ran, importin, compromises MT formation and neuronal morphogenesis. Finally, applying a Ran-importin signaling interfering compound phenocopies the effect of TPX2 depletion on MT dynamics. Together, these data suggest a model in which Ran-dependent TPX2 activation promotes acentrosomal MT nucleation in neurons.

No MeSH data available.