Advertisement

Cellular and Molecular Life Sciences

, Volume 68, Issue 12, pp 2089–2099 | Cite as

Nitric oxide stimulates human neural progenitor cell migration via cGMP-mediated signal transduction

  • Million Adane Tegenge
  • Thomas Dino Rockel
  • Ellen Fritsche
  • Gerd Bicker
Research Article

Abstract

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.

Keywords

Brain development Neurospheres Stem cells Cell motility Protein kinase G 

Notes

Acknowledgments

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).

References

  1. 1.
    Enikolopov G, Banerji J, Kuzin B (1999) Nitric oxide and Drosophila development. Cell Death Differ 6:956–963PubMedCrossRefGoogle Scholar
  2. 2.
    Cárdenas A, Moro MA, Hurtado O, Leza JC, Lizasoain I (2005) Dual role of nitric oxide in adult neurogenesis. Brain Res Brain Res Rev 50:1–6PubMedCrossRefGoogle Scholar
  3. 3.
    Bicker G (2005) STOP and GO with NO: nitric oxide as a regulator of cell motility in simple brains. Bioessays 27:495–505PubMedCrossRefGoogle Scholar
  4. 4.
    Madhusoodanan KS, Murad F (2007) NO-cGMP signalling and regenerative medicine involving stem cells. Neurochem Res 32:681–694PubMedCrossRefGoogle Scholar
  5. 5.
    Garthwaite J (2008) Concepts of neural nitric oxide-mediated transmission. Eur J Neurosci 27:2783–2802PubMedCrossRefGoogle Scholar
  6. 6.
    Jurado S, Sanchez-Prieto J, Torres M (2003) Differential expression of NO-sensitive guanylyl cyclase subunits during the development of rat cerebellar granule cells: regulation via N-methyl-d-aspartate receptors. J Cell Sci 116:3165–3175PubMedCrossRefGoogle Scholar
  7. 7.
    Tanaka M, Yoshida S, Yano M, Hanaoka F (1994) Roles of endogenous nitric oxide in cerebellar cortical development in slice cultures. Neuroreport 5:2049–2052PubMedCrossRefGoogle Scholar
  8. 8.
    Haase A, Bicker G (2003) Nitric oxide and cyclic nucleotides are regulators of neuronal migration in an insect embryo. Development 130:3977–3987PubMedCrossRefGoogle Scholar
  9. 9.
    Peunova N, Scheinker V, Ravi K, Enikolopov G (2007) Nitric oxide coordinates cell proliferation and cell movements during early development of Xenopus. Cell Cycle 6:3132–3144PubMedCrossRefGoogle Scholar
  10. 10.
    Knipp S, Bicker G (2009) Regulation of enteric neuron migration by the gaseous messenger molecules CO and NO. Development 136:85–93PubMedCrossRefGoogle Scholar
  11. 11.
    Moreno-López B, Noval JA, González-Bonet LG, Estrada C (2000) Morphological bases for a role of nitric oxide in adult neurogenesis. Brain Res 869:244–250PubMedCrossRefGoogle Scholar
  12. 12.
    Gutièrrez-Mecinas M, Crespo C, Blasco-Ibáñez JM, Nácher J, Varea E, Martínez-Guijarro FJ (2007) Migrating neuroblasts of the rostral migratory stream are putative targets for the action of nitric oxide. Eur J Neurosci 26:392–402PubMedCrossRefGoogle Scholar
  13. 13.
    Bredt DS, Snyder SH (1994) Transient nitric oxide synthase neurons in embryonic cerebral cortical plate, sensory ganglia, and olfactory epithelium. Neuron 13:301–313PubMedCrossRefGoogle Scholar
  14. 14.
    Nott A, Watson PM, Robinson JD, Crepaldi L, Riccio A (2008) S-Nitrosylation of histone deacetylase 2 induces chromatin remodelling in neurons. Nature 455:411–415PubMedCrossRefGoogle Scholar
  15. 15.
    Judas M, Sestan N, Kostović I (1999) Nitrinergic neurons in the developing and adult human telencephalon: transient and permanent patterns of expression in comparison to other mammals. Microsc Res Tech 45:401–419PubMedCrossRefGoogle Scholar
  16. 16.
    Foster JA, Phelps PE (2000) Neurons expressing NADPH-diaphorase in the developing human spinal cord. J Comp Neurol 427:417–427PubMedCrossRefGoogle Scholar
  17. 17.
    Fertuzinhos S, Krsnik Z, Kawasawa YI, Rasin MR, Kwan KY, Chen JG, Judas M, Hayashi M, Sestan N (2009) Selective depletion of molecularly defined cortical interneurons in human holoprosencephaly with severe striatal hypoplasia. Cereb Cortex 19:2196–21207PubMedCrossRefGoogle Scholar
  18. 18.
    Fritsche E, Cline JE, Nguyen NH, Scanlan TS, Abel J (2005) Polychlorinated biphenyls disturb differentiation of normal human neural progenitor cells: clue for involvement of thyroid hormone receptors. Environ Health Perspect 113:871–876PubMedCrossRefGoogle Scholar
  19. 19.
    Moors M, Cline JE, Abel J, Fritsche E (2007) ERK-dependent and independent pathways trigger human neural progenitor cell migration. Toxicol Appl Pharmacol 221:57–67PubMedCrossRefGoogle Scholar
  20. 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
  21. 21.
    Tegenge MA, Bicker G (2009) Nitric oxide and cGMP signal transduction positively regulates the motility of human neuronal precursor (NT2) cells. J Neurochem 110:1828–1841PubMedCrossRefGoogle Scholar
  22. 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
  23. 23.
    Evgenov OV, Pacher P, Schmidt PM, Haskó G, Schmidt HH, Stasch JP (2006) NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential. Nat Rev Drug Discov 5:755–768PubMedCrossRefGoogle Scholar
  24. 24.
    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 117:1131–1138PubMedCrossRefGoogle Scholar
  25. 25.
    Lauffenburger DA, Horwitz AF (1996) Cell migration: a physically integrated molecular process. Cell 84:359–369PubMedCrossRefGoogle Scholar
  26. 26.
    Brannen CL, Sugaya K (2000) In vitro differentiation of multipotent human neural progenitors in serum-free medium. Neuroreport 11:1123–1128PubMedCrossRefGoogle Scholar
  27. 27.
    Rakic P (2009) Evolution of the neocortex: a perspective from developmental biology. Nat Rev Neurosci 10:724–735PubMedCrossRefGoogle Scholar
  28. 28.
    Trimm KR, Rehder V (2004) Nitric oxide acts as a slow-down and search signal in developing neurites. Eur J Neurosci 19:809–818PubMedCrossRefGoogle Scholar
  29. 29.
    Elferink JG, VanUffelen BE (1996) The role of cyclic nucleotides in neutrophil migration. Gen Pharmacol 27:387–393PubMedGoogle Scholar
  30. 30.
    Borán MS, García A (2007) The cyclic GMP-protein kinase G pathway regulates cytoskeleton dynamics and motility in astrocytes. J Neurochem 102:216–230PubMedCrossRefGoogle Scholar
  31. 31.
    Sawada N, Itoh H, Yamashita J, Doi K, Inoue M, Masatsugu K, Fukunaga Y, Sakaguchi S, Sone M, Yamahara K, Yurugi T, Nakao K (2001) cGMP-dependent protein kinase phosphorylates and inactivates RhoA. Biochem Biophys Res Commun 280:798–805PubMedCrossRefGoogle Scholar
  32. 32.
    Gudi T, Chen JC, Casteel DE, Seasholtz TM, Boss GR, Pilz RB (2002) cGMP-dependent protein kinase inhibits serum-response element-dependent transcription by inhibiting rho activation and functions. J Biol Chem 277:37382–37393PubMedCrossRefGoogle Scholar
  33. 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
  34. 34.
    Lindsay SL, Ramsey S, Aitchison M, Renné T, Evans TJ (2007) Modulation of lamellipodial structure and dynamics by NO-dependent phosphorylation of VASP Ser239. J Cell Sci 120:3011–3021PubMedCrossRefGoogle Scholar
  35. 35.
    Chen H, Levine YC, Golan DE, Michel T, Lin AJ (2007) ANP-initiated cGMP pathways regulate VASP phosphorylation and angiogenesis in vascular endothelium. J Biol Chem 283:4439–4447PubMedCrossRefGoogle Scholar
  36. 36.
    Huang PL, Dawson TM, Bredt DS, Snyder SH, Fishman MC (1993) Targeted disruption of the neuronal nitric oxide synthase gene. Cell 75:1273–1286PubMedCrossRefGoogle Scholar
  37. 37.
    Brown C, Pan X, Hassid A (1999) Nitric oxide and C-type atrial natriuretic peptide stimulate primary aortic smooth muscle cell migration via a cGMP-dependent mechanism: relationship to microfilament dissociation and altered cell morphology. Circ Res 84:655–667PubMedGoogle Scholar
  38. 38.
    Ignarro LJ (2000) Nitric oxide, biology and pathobiology. Academic Press, San Diego, pp 300–380Google Scholar
  39. 39.
    Gally JA, Montague PR, Reeke GN Jr, Edelman GM (1996) The NO hypothesis: possible effects of a short-lived, rapidly diffusible signal in the development and function of the nervous system. Proc Natl Acad Sci USA 87:3547–3551CrossRefGoogle Scholar
  40. 40.
    Gibson NJ, Rössler W, Nighorn AJ, Oland LA, Hildebrand JG, Tolbert LP (2001) Neuron-glia communication via nitric oxide is essential in establishing antennal-lobe structure in Manduca sexta. Dev Biol 240:326–339PubMedCrossRefGoogle Scholar
  41. 41.
    Traister A, Abashidze S, Gold V, Plachta N, Karchovsky E, Patel K, Weil M (2002) Evidence that nitric oxide regulates cell-cycle progression in the developing chick neuroepithelium. Dev Dyn 225:271–276PubMedCrossRefGoogle Scholar
  42. 42.
    Zhang R, Zhang L, Zhang Z, Wang Y, Lu M, Lapointe M, Chopp M (2001) A nitric oxide donor induces neurogenesis and reduces functional deficits after stroke in rats. Ann Neurol 50:602–611PubMedCrossRefGoogle Scholar
  43. 43.
    Cui X, Chen J, Zacharek A, Roberts C, Yang Y, Chopp M (2009) Nitric oxide donor up-regulation of SDF1/CXCR4 and Ang1/Tie2 promotes neuroblast cell migration after stroke. J Neurosci Res 87:86–95PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel AG 2010

Authors and Affiliations

  1. 1.Division of Cell Biology, Institute of PhysiologyUniversity of Veterinary Medicine HannoverHannoverGermany
  2. 2.Center for Systems Neuroscience (ZSN)HannoverGermany
  3. 3.Group of Molecular ToxicologyInstitut für Umweltmedizinische Forschung at the Heinrich Heine-University gGmbHDüsseldorfGermany
  4. 4.Department of DermatologyUniversity HospitalAachenGermany

Personalised recommendations