Nitric Oxide Mediated Signal Transduction in Networks of Human ...

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which were accompanied by differentiation into both neuronal and glial cells. Intriguingly, cells that migrate out respond to exogenous stimulation of NO and synthesize increasing level of cGMP. These results provide first experimental evidence that functional NO-sensitive sGC is expressed early during human brain development. The cGMP positive cells at the forefront of migration were co-stained for either nestin or GFAP but not for ��-tubulin. Thus, compared to NT2 cell culture that lack GFAP positive cells, the hNPCs may mimic aspects of radial neuroblast migration during human brain development. Application of small bioactive enzyme inhibitors and activators in human neurosphere culture implicate that NO/cGMP/PKG signaling is key regulator of neuronal progenitor migration. Compared to the NT2 cell culture, in hNPCs inverted U-shaped dose-response curve for the NO donor NOC-18 was obtained at relatively smaller dose range (1-100 µM). Our data demonstrate that at 10 µM NOC-18 appeared to facilitate neuronal progenitor cell migration while at relatively higher concentration (100 µM) inhibition of cell migration was observed. These result suggest that NO could play dual role on neuronal migration depending on the concentration. Such dual role of NO on cell migration and neurite outgrowth that depends on concentration has been reported previously (Elferink, and VanUffelen, 1996; Trimm and Rehder, 2004). Furthermore, we directly showed the involvement of sGC and PKG in NO induced facilitation of hNPCs migration. Here, coapplication of NO donor with enzyme inhibitors of sGC or PKG resulted in blocked of NO induced facilitation of hNPCs migration suggesting that low concentration of NO facilitates neuronal progenitor migration via sGC and PKG signaling pathway. In summary, this study provides the first evidence for the involvement of NO signaling in human neuronal development. Since neuronal migration is controlled by a complex combination of chemical signals, it would be interesting to comprehend how the NO signal regulates neuronal migration in combination with other known signals. Understanding the cellular and molecular mechanisms of neuronal migration may offer hopes to develop new therapeutic agents for human congential disorders associated with defective neuronal migration. Our findings have further implications in adult neurogenesis. In recent years research in NSC biology focus on restoration of damaged neural networks in the various neurodegenerative diseases by promoting endogenous neurogenesis or transplantation of NSC. To this end, manipulation of NO/cGMP signaling may facilitate migration and integration of endogenous or transplanted neuronal progenitor cells into the existing neuronal network which could promote functional recovery in various neurodegenerative diseases. 17
References Agulló, L., and García, A. (1992). Different receptors mediate stimulation of nitric oxide-dependent cyclic GMP formation in neurons and astrocytes in culture. Biochem. Biophys. Res. Commun 182, 1362-1368. Andrews, P. W. (1984). Retinoic acid induces neuronal differentiation of a cloned human embryonal carcinoma cell line in vitro. Dev. Biol 103, 285-293. Arnold, W. P., Mittal, C. K., Katsuki, S., and Murad, F. (1977). Nitric oxide activates guanylate cyclase and increases guanosine 3':5'-cyclic monophosphate levels in various tissue preparations. Proc. Natl. Acad. Sci. U.S.A 74, 3203-3207. Ayala, R., Shu, T., and Tsai, L. (2007). Trekking across the brain: the journey of neuronal migration. Cell 128, 29-43. Ball, E. E., and Truman, J. W. (1998). Developing grasshopper neurons show variable levels of guanylyl cyclase activity on arrival at their targets. J. Comp. Neurol 394, 1-13. Baltrons, M. A., Pedraza, C., Sardón, T., Navarra, M., and García, A. (2003). Regulation of NOdependent cyclic GMP formation by inflammatory agents in neural cells. Toxicol. Lett 139, 191-198. Bicker, G. (2001). Nitric oxide: an unconventional messenger in the nervous system of an orthopteroid insect. Arch. Insect Biochem. Physiol 48, 100-110. Bicker, G. (2005). STOP and GO with NO: nitric oxide as a regulator of cell motility in simple brains. Bioessays 27, 495-505. Blaise, G. A., Gauvin, D., Gangal, M., and Authier, S. (2005). Nitric oxide, cell signaling and cell death. Toxicology 208, 177-192. Boehning, D., and Snyder, S. H. (2003). Novel neural modulators. Annu. Rev. Neurosci 26, 105- 131. Bonanomi, D., Menegon, A., Miccio, A., Ferrari, G., Corradi, A., Kao, H., Benfenati, F., and Valtorta, F. (2005). Phosphorylation of synapsin I by cAMP-dependent protein kinase controls synaptic vesicle dynamics in developing neurons. J. Neurosci 25, 7299-7308. Borán, M. S., and García, A. (2007). The cyclic GMP-protein kinase G pathway regulates cytoskeleton dynamics and motility in astrocytes. J. Neurochem 102, 216-230. Boucherie, C., and Hermans, E. (2009). Adult stem cell therapies for neurological disorders: benefits beyond neuronal replacement? J. Neurosci. Res 87, 1509-1521. Bredt, D. S., Hwang, P. M., and Snyder, S. H. (1990). Localization of nitric oxide synthase indicating a neural role for nitric oxide. Nature 347, 768-770. Bredt, D. S., and Snyder, S. H. (1989). Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum. Proc. Natl. Acad. Sci. U.S.A 86, 9030-9033. Bredt, D. S., and Snyder, S. H. (1994). Transient nitric oxide synthase neurons in embryonic cerebral cortical plate, sensory ganglia, and olfactory epithelium. Neuron 13, 301-313. 18
Page 1: Fehlerhafte Abgabe! Original Artike
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Fig. 1 The antibody against nNOS re
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Fig. 3 Immunocytochemical character
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Fig. 5 NO donor and cell membrane p
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NO/cGMP/PKG signaling mediate the m
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Bredt, D. S. and Snyder, S. H. (199
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Declaration I herewith declare that
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