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      Microtubule stabilization specifies initial neuronal polarization

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      The Journal of Cell Biology

      The Rockefeller University Press

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          Abstract

          Axon formation is the initial step in establishing neuronal polarity. We examine here the role of microtubule dynamics in neuronal polarization using hippocampal neurons in culture. We see increased microtubule stability along the shaft in a single neurite before axon formation and in the axon of morphologically polarized cells. Loss of polarity or formation of multiple axons after manipulation of neuronal polarity regulators, synapses of amphids defective (SAD) kinases, and glycogen synthase kinase-3β correlates with characteristic changes in microtubule turnover. Consistently, changing the microtubule dynamics is sufficient to alter neuronal polarization. Application of low doses of the microtubule-destabilizing drug nocodazole selectively reduces the formation of future dendrites. Conversely, low doses of the microtubule-stabilizing drug taxol shift polymerizing microtubules from neurite shafts to process tips and lead to the formation of multiple axons. Finally, local stabilization of microtubules using a photoactivatable analogue of taxol induces axon formation from the activated area. Thus, local microtubule stabilization in one neurite is a physiological signal specifying neuronal polarization.

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          Most cited references 45

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          The establishment of polarity by hippocampal neurons in culture.

          By the end of the first week in culture, hippocampal neurons have established a single axon and several dendrites. These 2 classes of processes differ in their morphology, in their molecular composition, and in their synaptic polarity (Bartlett and Banker, 1984a, b; Caceres et al., 1984). We examined the events during the first week in culture that lead to the establishment of this characteristic form. Hippocampal cells were obtained from 18 d fetal rats, plated onto polylysine-treated coverslips, and maintained in a serum-free medium. The development of individual cells was followed by sequential photography at daily intervals until both axons and dendrites had been established; identification of the processes was confirmed by immunostaining for MAP2, a dendritic marker. Time-lapse video recording was used to follow the early stages of process formation. Hippocampal neurons acquired their characteristic form by a stereotyped sequence of developmental events. The cells first established several, apparently identical, short processes. After several hours, one of the short processes began to grow very rapidly; it became the axon. The remaining processes began to elongate a few days later and grew at a much slower rate. They became the cell's dendrites. Neurons that arose following mitosis in culture underwent this same sequence of developmental events. In a few instances, 2 processes from a cell exhibited the rapid growth typical of axons, but only one maintained this growth; the other retracted and became a dendrite. Axons branched primarily by the formation of collaterals, not by bifurcation of growth cones. As judged by light microscopy, processes are not specified as axons or dendrites when they arise. The first manifestation of neuronal polarity is the acquisition of axonal characteristics by one of the initial processes; subsequently the remaining processes become dendrites.
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            The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling.

            Glycogen synthase kinase-3beta (GSK3beta) is a fascinating enzyme with an astoundingly diverse number of actions in intracellular signaling systems. GSK3beta activity is regulated by serine (inhibitory) and tyrosine (stimulatory) phosphorylation, by protein complex formation, and by its intracellular localization. GSK3beta phosphorylates and thereby regulates the functions of many metabolic, signaling, and structural proteins. Notable among the signaling proteins regulated by GSK3beta are the many transcription factors, including activator protein-1, cyclic AMP response element binding protein, heat shock factor-1, nuclear factor of activated T cells, Myc, beta-catenin, CCAAT/enhancer binding protein, and NFkappaB. Lithium, the primary therapeutic agent for bipolar mood disorder, is a selective inhibitor of GSK3beta. This raises the possibility that dysregulation of GSK3beta and its inhibition by lithium may contribute to the disorder and its treatment, respectively. GSK3beta has been linked to all of the primary abnormalities associated with Alzheimer's disease. These include interactions between GSK3beta and components of the plaque-producing amyloid system, the participation of GSK3beta in phosphorylating the microtubule-binding protein tau that may contribute to the formation of neurofibrillary tangles, and interactions of GSK3beta with presenilin and other Alzheimer's disease-associated proteins. GSK3beta also regulates cell survival, as it facilitates a variety of apoptotic mechanisms, and lithium provides protection from many insults. Thus, GSK3beta has a central role regulating neuronal plasticity, gene expression, and cell survival, and may be a key component of certain psychiatric and neurodegenerative diseases.
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              GSK-3beta regulates phosphorylation of CRMP-2 and neuronal polarity.

              Neurons are highly polarized and comprised of two structurally and functionally distinct parts, an axon and dendrites. We previously showed that collapsin response mediator protein-2 (CRMP-2) is critical for specifying axon/dendrite fate, possibly by promoting neurite elongation via microtubule assembly. Here, we showed that glycogen synthase kinase-3beta (GSK-3beta) phosphorylated CRMP-2 at Thr-514 and inactivated it. The expression of the nonphosphorylated form of CRMP-2 or inhibition of GSK-3beta induced the formation of multiple axon-like neurites in hippocampal neurons. The expression of constitutively active GSK-3beta impaired neuronal polarization, whereas the nonphosphorylated form of CRMP-2 counteracted the inhibitory effects of GSK-3beta, indicating that GSK-3beta regulates neuronal polarity through the phosphorylation of CRMP-2. Treatment of hippocampal neurons with neurotrophin-3 (NT-3) induced inactivation of GSK-3beta and dephosphorylation of CRMP-2. Knockdown of CRMP-2 inhibited NT-3-induced axon outgrowth. These results suggest that NT-3 decreases phosphorylated CRMP-2 and increases nonphosphorylated active CRMP-2, thereby promoting axon outgrowth.
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                Author and article information

                Journal
                J Cell Biol
                jcb
                The Journal of Cell Biology
                The Rockefeller University Press
                0021-9525
                1540-8140
                11 February 2008
                : 180
                : 3
                : 619-632
                Affiliations
                Axonal Growth and Regeneration, Max Planck Institute of Neurobiology, 82152 Martinsried, Germany
                Author notes

                Correspondence to F. Bradke: fbradke@ 123456neuro.mpg.de

                Article
                200707042
                10.1083/jcb.200707042
                2234250
                18268107
                Copyright © 2008, The Rockefeller University Press
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                Research Articles
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                Cell biology

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