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      Neurotrophin Regulation of β-Actin mRNA and Protein Localization within Growth Cones

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          Abstract

          Neurotrophins play an essential role in the regulation of actin-dependent changes in growth cone shape and motility. We have studied whether neurotrophin signaling can promote the localization of β-actin mRNA and protein within growth cones. The regulated localization of specific mRNAs within neuronal processes and growth cones could provide a mechanism to modulate cytoskeletal composition and growth cone dynamics during neuronal development. We have previously shown that β-actin mRNA is localized in granules that were distributed throughout processes and growth cones of cultured neurons. In this study, we demonstrate that the localization of β-actin mRNA and protein to growth cones of forebrain neurons is stimulated by neurotrophin-3 (NT-3). A similar response was observed when neurons were exposed to forskolin or db-cAMP, suggesting an involvement of a cAMP signaling pathway. NT-3 treatment resulted in a rapid and transient stimulation of PKA activity that preceded the localization of β-actin mRNA. Localization of β-actin mRNA was blocked by prior treatment of cells with Rp-cAMP, an inhibitor of cAMP-dependent protein kinase A. Depolymerization of microtubules, but not microfilaments, inhibited the NT-3–induced localization of β-actin mRNA. These results suggest that NT-3 activates a cAMP-dependent signaling mechanism to promote the microtubule-dependent localization of β-actin mRNA within growth cones.

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          Most cited references 55

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          cAMP-induced switching in turning direction of nerve growth cones.

           M Poo,  J. Song,  G. Ming (1997)
          Development of the nervous system depends on the correct pathfinding and target recognition by the growing tip of an axon, the growth cone. Diffusible or substrate-bound molecules present in the environment may serve as either attractants or repellents to influence the direction of growth-cone extension. Here we report that differences in cyclic-AMP-dependent activity in a neuron may result in opposite turning of the growth cone in response to the same guidance cue. A gradient of brain-derived neurotrophic factor normally triggers an attractive turning response of the growth cone of Xenopus spinal neurons in culture, but the same gradient induces repulsive turning of these growth cones in the presence of a competitive analogue of cAMP or of a specific inhibitor of protein kinase A. This cAMP-dependent switch of the turning response was also found for turning induced by acetylcholine, but not for the turning induced by neurotrophin-3 (NT-3). Thus, in the presence of other factors that modulate neuronal cAMP-dependent activity, the same guidance cue may trigger opposite turning behaviours of the growth cone during its pathfinding in the nervous system.
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            cAMP-dependent growth cone guidance by netrin-1.

            Netrin-1 is known to function as a chemoattractant for several classes of developing axons and as a chemorepellent for other classes of axons, apparently dependent on the receptor type expressed by responsive cells. In culture, growth cones of embryonic Xenopus spinal neurons exhibited chemoattractive turning toward the source of netrin-1 but showed chemorepulsive responses in the presence of a competitive analog of cAMP or an inhibitor of protein kinase A. Both attractive and repulsive responses were abolished by depleting extracellular calcium and by adding a blocking antibody against the netrin-1 receptor Deleted in Colorectal Cancer. Thus, nerve growth cones may respond to the same guidance cue with opposite turning behavior, dependent on other coincident signals that set the level of cytosolic cAMP.
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              Translocation of RNA granules in living neurons.

              Sorting of RNAs to specific subcellular loci occurs in diverse settings from fly oocytes to mammalian neurons. Using the membrane-permeable nucleic acid stain SYTO 14, we directly visualized the translocation of endogenous RNA in living cells. Labeled RNA was distributed nonrandomly as discrete granules in neuronal processes. The labeled granules colocalized with poly(A+) mRNA, with the 60S ribosomal subunit, and with elongation factor 1alpha, suggesting that granules represent a translational unit. A subset of labeled granules colocalized with beta-actin mRNA. Correlative light and electron microscopy indicated that the fluorescent granules corresponded to clusters of ribosomes at the ultrastructural level. Poststaining of sections with heavy metals confirmed the presence of ribosomes within these granules. In living neurons, a subpopulation of RNA granules was motile during the observation period. They moved at an average rate of 0.1 microm/sec. In young cultures their movements were exclusively anterograde, but after 7 d in culture, one-half of the motile granules moved in the retrograde direction. Granules in neurites were delocalized after treatment with microtubule-disrupting drugs. These results raise the possibility of a cellular trafficking system for the targeting of RNA in neurons.
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                Author and article information

                Contributors
                Journal
                J Cell Biol
                The Journal of Cell Biology
                The Rockefeller University Press
                0021-9525
                1540-8140
                4 October 1999
                : 147
                : 1
                : 59-70
                Affiliations
                [a ]Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461
                [b ]Department of Anatomy, Albert Einstein College of Medicine, Bronx, New York 10461
                Article
                9907054
                2164987
                10508855
                © 1999 The Rockefeller University Press
                Categories
                Original Article

                Cell biology

                neurite outgrowth, growth cone, neurotrophin, β-actin, mrna localization

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