title: Nurr1 blocks the mitogenic effect of FGF-2 and EGF, inducing olfactory bulb neural stem cells to adopt dopaminergic and dopaminergic-GABAergic neuronal phenotypes.
abstract: The transcription factor Nurr1 is expressed in the mouse olfactory bulb (OB), although it remains unknown whether it influences the generation of dopaminergic neurons (DA) (DA neurons) in cells isolated from this brain region. We found that expressing Nurr1 in proliferating olfactory bulb stem cells (OBSCs) produces a marked inhibition of cell proliferation and the generation of immature neurons immunoreactive for tyrosine hydroxylase (TH) concomitant with marked upregulations of Th, Dat, Gad, and Fgfr2 transcripts. In long-term cultures, these cells develop neurochemical and synaptic markers of mature-like mesencephalic DA neurons, expressing GIRK2, VMAT2, DAT, calretinin, calbindin, synapsin-I, and SV2. Concurring with the increase in both Th and Gad expression, a subpopulation of induced cells was both TH- and GAD-immunoreactive indicating that they are dopaminergic-GABAergic neurons. Indeed, these cells could mature to express VGAT, suggesting they can uptake and store GABA in vesicles. Remarkably, the dopamine D1 receptor agonist SKF-38393 induced c-Fos in TH(+) cells and dopamine release was detected in these cultures under basal and KCl-evoked conditions. By contrast, cotransducing the Neurogenin2 and Nurr1 transcription factors produced a significant decrease in the number of TH-positive neurons. Our results indicate that Nurr1 overexpression in OBSCs induces the formation of two populations of mature dopaminergic neurons with features of the ventral mesencephalon or of the OB, capable of responding to functional dopaminergic stimuli and of releasing dopamine. They also suggest that the accumulation of Fgfr2 by Nurr1 in OBSCs may be involved in the generation of DA neurons.
authors.affiliation: Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Vergaño-Vera
authors.affiliation: Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Díaz-Guerra
authors.affiliation: Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Rodríguez-Traver
authors.affiliation: Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Héctor R
authors.initials: HR
authors.lastname: Méndez-Gómez
authors.affiliation: Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Óscar
authors.initials: Ó
authors.lastname: Solís
authors.affiliation: Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Jaime
authors.initials: J
authors.lastname: Pignatelli
authors.affiliation: Transgenic Core, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: James
authors.initials: J
authors.lastname: Pickel
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang university, Seoul, Korea.
authors.forename: Sang-Hun
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Rosario
authors.initials: R
authors.lastname: Moratalla
authors.affiliation: Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Vicario-Abejón
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000502:physiology*; D004815:Epidermal Growth Factor / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D059330:GABAergic Neurons / Q000187:drug effects / Q000502:physiology*; D008810:Mice, Inbred C57BL; D008938:Mitosis / Q000187:drug effects / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects / Q000502:physiology*; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000378:metabolism*; D009830:Olfactory Bulb / Q000187:drug effects / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004815:Epidermal Growth Factor; D016222:Fibroblast Growth Factor 2; D009419:Nerve Tissue Proteins; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D014446:Tyrosine 3-Monooxygenase; C102938:Neurog2 protein, mouse; C539883:Nr4a2 protein, mouse
keywords: Fgfr2; GABAergic neurons; dopaminergic neurons; neural stem cells; transcription factors