Nitric oxide stimulates human neural progenitor cell migration via cGMP-mediated signal transduction
- 335 Downloads
Neuronal migration is one of the most critical processes during early brain development. The gaseous messenger nitric oxide (NO) has been shown to modulate neuronal and glial migration in various experimental models. Here, we analyze a potential role for NO signaling in the migration of fetal human neural progenitor cells. Cells migrate out of cultured neurospheres and differentiate into both neuronal and glial cells. The neurosphere cultures express neuronal nitric oxide synthase and soluble guanylyl cyclase that produces cGMP upon activation with NO. By employing small bioactive enzyme activators and inhibitors in both gain and loss of function experiments, we show NO/cGMP signaling as a positive regulator of migration in neurosphere cultures of early developing human brain cells. Since NO signaling regulates cell movements from developing insects to mammalian nervous systems, this transduction pathway may have evolutionary conserved functions.
KeywordsBrain development Neurospheres Stem cells Cell motility Protein kinase G
We thank Dr J. de Vente for his kind gift of the cGMP antiserum, Dr. M. Stern for the discussion during the preparation of the manuscript, and Nadine Seiferth for technical support. We also like to acknowledge the contribution of Susanne Giersiefer to the experiment with the ROCK inhibitor. We thank Prech Uapinyoying for reading and correcting the manuscript. M.A. Tegenge received a Georg-Christoph-Lichtenberg scholarship from the Ministry for Science and Culture of Lower Saxony. This work was supported by the BMBF grants (013925C) to E. Fritsche (013925D) to G. Bicker and DFG grant (FG 1103, BI 262/16-1).
- 20.Moors M, Rockel TD, Abel J, Cline JE, Gassmann K, Schreiber T, Schuwald J, Weinmann N, Fritsche E (2009) Human neurospheres as three-dimensional cellular systems for developmental neurotoxicity testing. Environ Health Perspect 117:1131–1138Google Scholar
- 22.De Vente J, Steinbusch HW, Schipper J (1987) A new approach to immunocytochemistry of 3′, 5′′-cyclic guanosine monophosphate: preparation, specificity, and initial application of a new antiserum against formaldehyde-fixed 3′, 5′-cyclic guanosine monophosphate. Neuroscience 22:361–373PubMedCrossRefGoogle Scholar
- 33.Sporbert A, Mertsch K, Smolenski A, Haseloff RF, Schönfelder G, Paul M, Ruth P, Walter U, Blasig IE (1999) Phosphorylation of vasodilator-stimulated phosphoprotein: a consequence of nitric oxide- and cGMP-mediated signal transduction in brain capillary endothelial cells and astrocytes. Brain Res Mol Brain Res 67:258–266PubMedCrossRefGoogle Scholar
- 38.Ignarro LJ (2000) Nitric oxide, biology and pathobiology. Academic Press, San Diego, pp 300–380Google Scholar