Nucleating microtubules in neurons: Challenges and solutions.

The highly polarized morphology of neurons is crucial for their function and involves formation of two distinct types of cellular extensions, the axonal and dendritic compartments. An important effector required for the morphogenesis and maintenance and thus the identity of axons and dendrites is the microtubule cytoskeleton. Microtubules in axons and dendrites are arranged with distinct polarities, to allow motor-dependent, compartment-specific sorting of cargo. Despite the importance of the microtubule cytoskeleton in neurons, the molecular mechanisms that generate the intricate compartment-specific microtubule configurations remain largely obscure. Work in other cell types has identified microtubule nucleation, the de novo formation of microtubules, and its spatio-temporal regulation as essential for the proper organization of the microtubule cytoskeleton. Whereas regulation of microtubule nucleation usually involves microtubule organizing centers such as the centrosome, neurons seem to rely largely on decentralized nucleation mechanisms. In this review, I will discuss recent advances in deciphering nucleation mechanisms in neurons, how they contribute to the arrangement of microtubules with specific polarities, and how this affects neuron morphogenesis. While this work has shed some light on these important processes, we are far from a comprehensive understanding. Thus, to provide a coherent model, my discussion will include both well-established mechanisms and mechanisms with more limited supporting data. Finally, I will also highlight important outstanding questions for future investigation.