One of the key questions of neurobiology is how neurons polarize to acquire two molecularly and functionally distinct compartments that emerge from the cell body: a single axon and multiple dendrites, which provide the basis for unidirectional signal transmission in the mature nervous system.
Cultures of hippocampal pyramidal neurons have been used as a model system to analyse the cellular and molecular mechanisms that underlie the development and maintenance of neuronal polarity.
Phosphoinositide 3-kinase (PI3K) signalling, local actin instability in growth cones and the selective stabilization of microtubules in a particular neurite have emerged as crucial events triggering axon specification.
Neuronal microtubules are regulated by many proteins, including assembly promoting factors, such as collapsin response mediator protein 2 (CRMP2); stabilizers, such as structural or classical microtubule-associated proteins (MAPs); destabilizing factors, such as stathmin; microtubule severing proteins, such as katanin; plus end tracking proteins, such as adenomatous polyposis coli and end-binding protein 1 (also known as MAPRE1); microtubule-based motors of the kinesin and dynein superfamilies; and multiple kinases, such as glycogen synthase kinase 3, LKB1 (also known as STK11) and LKB1's interacting partner STRAD.
Stable microtubules provide nucleation seeds for microtubule assembly and protrusion, as well as tracks for the preferential binding of microtubule-based motors that transport membrane-bound organelles and regulatory macromolecular complexes during axon formation.
Dynamic microtubules in growth cones act as sensors of cellular conditions by extending in various directions in the peripheral actin-rich domain. Some of them interact with components of the cell cortex to activate signalling pathways required for regulating actin dynamics and axonal growth.
The plus ends of microtubules have a central role in the interactions that occur between microtubules and the actin cytoskeleton, which are required for neuronal polarization. Plus end tracking proteins associate and specifically accumulate at the plus ends of microtubules, and control microtubule dynamics, growth directionality and interactions with components of the cell cortex.
Positive and negative feedback loops mediated by small Rho GTPases, guanine nucleotide exchange factors, GTPase activating proteins and their downstream effectors also regulate the crosstalk between microtubules and actin filaments that is required for axon and dendrite formation.
Differences in the orientation of microtubules distinguish axons from dendrites, and the minus end-based motor dynein has a crucial role in organizing dendritic arbors and the uniform orientation of axonal microtubules.
Microtubules have also been implicated in regulating the conversion of a motile growth cone into a synaptic terminal. Recently, dynamic microtubules have been implicated in spine development.
During the past decade enormous advances have been made in our understanding of the basic molecular machinery that is involved in the development of neuronal polarity. Far from being mere structural elements, microtubules are emerging as key determinants of neuronal polarity. Here we review the current understanding of the regulation of microtubule assembly, organization and dynamics in axons and dendrites. These studies provide new insight into microtubules' function in neuronal development and their potential contribution to plasticity.
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The authors acknowledge support from the National Research Council of Argentina (CONICET) and the Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT). We also thank members of our laboratory for helpful discussions about neuronal polarity.
- Cell cortex
The region of a cell that lies beneath the plasma membrane and contains a network of actin filaments and associated proteins.
- Microtubule capture
The interaction between microtubules and components of the cell cortex that results in stabilization of the microtubules.
- Microtubule severing
A process through which enzymes break the lattice of the microtubule to generate multiple short microtubules that have the potential to move and reconfigure.
The formation of new microtubules from α-and β-tubulin heterodimers. It requires γ-tubulin protein complexes.
A microtubule stabilizing agent and mitotic inhibitor used in cancer therapy.
- Lamellipodial veil
A flattened and highly dynamic cell expansion that contains abundant branched and cross-linked actin filaments. It is particularly prominent at the leading edge of migrating cells and growth cones.
- Actin ribs
Short actin filament bundles that are radially oriented and abundant in small growth cones.
A natural alkaloid that binds to tubulin and inhibits microtubule formation.
- Cytochalasin D
A cell-permeable and potent inhibitor of actin polymerization.
- Retrograde actin flow
Myosin-driven, retrograde (relative to the substratum) movement of actin filaments in lamellipodia; it has a role in cell motility and growth cone advance.
- Actin arcs
Arc-shaped actin filament bundles that are found at the transition zone between the central and peripheral domains of growth cones. Actin arcs undergo myosin II-driven contraction to compress and bundle microtubules in the growth cone central domain.
- Hairpin microtubule loop
A looped portion of microtubule in a stable synaptic bouton. Disassembly of hairpin microtubule loops is associated with boutons undergoing division or with sites of sprouting.
- Synaptic bouton
A button-like terminal enlargement of an axon that contains synaptic vesicles filled with neurotransmitters.
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Conde, C., Cáceres, A. Microtubule assembly, organization and dynamics in axons and dendrites. Nat Rev Neurosci 10, 319–332 (2009). https://doi.org/10.1038/nrn2631
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