title: Nitric oxide stimulates the proliferation of neural stem cells bypassing the epidermal growth factor receptor.
abstract: Nitric oxide (NO) was described to inhibit the proliferation of neural stem cells. Some evidence suggests that NO, under certain conditions, can also promote cell proliferation, although the mechanisms responsible for a potential proliferative effect of NO in neural stem cells have remained unaddressed. In this work, we investigated and characterized the proliferative effect of NO in cell cultures obtained from the mouse subventricular zone. We found that the NO donor NOC-18 (10 microM) increased cell proliferation, whereas higher concentrations (100 microM) inhibited cell proliferation. Increased cell proliferation was detected rapidly following exposure to NO and was prevented by blocking the mitogen-activated kinase (MAPK) pathway, independently of the epidermal growth factor (EGF) receptor. Downstream of the EGF receptor, NO activated p21Ras and the MAPK pathway, resulting in a decrease in the nuclear presence of the cyclin-dependent kinase inhibitor 1, p27(KIP1), allowing for cell cycle progression. Furthermore, in a mouse model that shows increased proliferation of neural stem cells in the hippocampus following seizure injury, we observed that the absence of inducible nitric oxide synthase (iNOS(-/-) mice) prevented the increase in cell proliferation observed following seizures in wild-type mice, showing that NO from iNOS origin is important for increased cell proliferation following a brain insult. Overall, we show that NO is able to stimulate the proliferation of neural stem cells bypassing the EGF receptor and promoting cell division. Moreover, under pathophysiological conditions in vivo, NO from iNOS origin also promotes proliferation in the hippocampus.
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: Bruno Pereira
authors.initials: BP
authors.lastname: Carreira
authors.forename: Maria Inês
authors.initials: MI
authors.lastname: Morte
authors.forename: Angela
authors.initials: A
authors.lastname: Inácio
authors.forename: Gabriel
authors.initials: G
authors.lastname: Costa
authors.forename: Joana
authors.initials: J
authors.lastname: Rosmaninho-Salgado
authors.forename: Fabienne
authors.initials: F
authors.lastname: Agasse
authors.forename: Anália
authors.initials: A
authors.lastname: Carmo
authors.forename: Patrícia
authors.initials: P
authors.lastname: Couceiro
authors.forename: Patrik
authors.initials: P
authors.lastname: Brundin
authors.forename: António Francisco
authors.initials: AF
authors.lastname: Ambrósio
authors.forename: Caetana Monteiro
authors.initials: CM
authors.lastname: Carvalho
authors.forename: Inês Maria
authors.initials: IM
authors.lastname: Araújo
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*
chemical_list: D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D066246:ErbB Receptors