Nitric oxide and cGMP signal transduction positively regulates the motility of human neuronal precursor (NT2) cells.
Developmental studies in both vertebrates and invertebrates implicate an involvement of nitric oxide (NO) signaling in cell proliferation, neuronal motility, and synaptic maturation. However, it is unknown whether NO plays a role in the development of the human nervous system. We used a model of human neuronal precursor cells from a well-characterized teratocarcinoma cell line (NT2). The precursor cells proliferate during retinoic acid treatment as spherical aggregate culture that stains for nestin and betaIII-tubulin. Cells migrate out of the aggregates to acquire fully differentiated neuronal phenotypes. The cells express neuronal nitric oxide synthase and soluble guanylyl cyclase (sGC), an enzyme that synthesizes cGMP upon activation by NO. The migration of the neuronal precursor cell is blocked by the use of nNOS, sGC, and protein kinase G (PKG) inhibitors. Inhibition of sGC can be rescued by a membrane permeable analog of cGMP. In gain of function experiments the application of a NO donor and cGMP analog facilitate cell migration. Our results from the differentiating NT2 model neurons point towards a vital role of the NO/cGMP/PKG signaling cascade as positive regulator of cell migration in the developing human brain.
Tegenge
Million Adane
MA
Division of Cell Biology, Institute of Physiology, University of Veterinary Medicine Hannover, Hannover, Germany.
Bicker
Gerd
G
D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008954:Models, Biological; D014411:Neoplastic Stem Cells / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D009603:Nitroso Compounds / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013873:Thionucleotides / Q000494:pharmacology; D013997:Time Factors; D014212:Tretinoin / Q000494:pharmacology; D014404:Tubulin / Q000378:metabolism
D004791:Enzyme Inhibitors; C093285:NOC 18; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; C498585:TUBB3 protein, human; D013873:Thionucleotides; D014404:Tubulin; C083763:8-bromoguanosino-3',5'-cyclic monophosphorothioate; D009569:Nitric Oxide; D014212:Tretinoin; D052248:Nitric Oxide Synthase Type I; D006152:Cyclic GMP