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.ĭifferences 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. 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. 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. Some of them interact with components of the cell cortex to activate signalling pathways required for regulating actin dynamics and axonal growth. 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.ĭynamic microtubules in growth cones act as sensors of cellular conditions by extending in various directions in the peripheral actin-rich domain. 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. 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. 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.Ĭultures 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.
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