Neuronal polarization: building and organizing the microtubule network

Abstract

The nervous system is the communication center of both humans and animals. It plays an essential role in functions such as memory, learning, movement, and among others our senses. Just like the rest of an organism is the nervous system also made out of cells. The cells of the nervous system are known as neurons, they form a communication network by making contacts with each other. The development and maturation of these neurons are essential for their functions, which can result in various diseases when failing. Understanding this development plays, among others, a crucial role in unrevealing diseases like Alzheimer's, ALS, spinal cord injuries, and even multiple sclerosis induced axon degeneration. One of the important processes during development is the polarization of an immature cell into a neuron with one axon (responsible for sending signals) and multiple dendrites (responsible for receiving signals). The skeleton of the cell (the cytoskeleton) plays an important role in the development of neurons by giving the cell structure, shape, rigidity, and mobility. Furthermore, the cytoskeleton serves as roads for intracellular transport of proteins and organelles. Tube like structures named microtubules form a key component of the cytoskeleton and are able to form an extensive network. This thesis gives new insights in processes that are involved in neuronal polarization. More specifically, we studied the role of the microtubule cytoskeleton and their associated proteins in organizing the microtubule network during development. This includes the role of the microtubule minus-end binding protein CAMSAP2 in non-centrosomal microtubule stabilization in neurons. We show that CAMSAP2 forms stretches along neuronal microtubule minus-ends and stabilizes these non-centrosomal microtubules in neurons, thereby playing a critical role for dendrite development and axon specification in both neuronal cell cultures and the developing mouse brain. In addition, we describe the identification of the microtubule associated protein TRIM46 as an autoantigen that specifically localizes to the proximal axon of newly specified axons early during the polarization process. Using various microscopy techniques we show that TRIM46 fulfills an important function between MAP2 and Tau at the proximal axon in forming parallel microtubule arrays, in axonal cargo trafficking, and in forming electron dense microtubule cross bridges. Our experiments show that TRIM46 is essential for neuronal polarity and axon specification in both neuronal cell cultures as well as the developing mouse brain. In short, both CAMSAP2 and TRIM46 play an important role in building and organizing the microtubule network in neurons. By fulfilling this role, they are required for proper neuron development and possibly even protect against neuron degeneration as seen in diseases such as Alzheimer's, ALS, and multiple sclerosis.