title: Activation of developmental nuclear fibroblast growth factor receptor 1 signaling and neurogenesis in adult brain by α7 nicotinic receptor agonist.
abstract: Reactivation of endogenous neurogenesis in the adult brain or spinal cord holds the key for treatment of central nervous system injuries and neurodegenerative disorders, which are major health care issues for the world's aging population. We have previously shown that activation of developmental integrative nuclear fibroblast growth factor receptor 1 (FGFR1) signaling (INFS), via gene transfection, reactivates neurogenesis in the adult brain by promoting neuronal differentiation of brain neural stem/progenitor cells (NS/PCs). In the present study, we report that targeting the α7 nicotinic acetylcholine receptors (α7nAChRs) with a specific TC-7020 agonist led to a robust accumulation of endogenous FGFR1 in the cell nucleus. Nuclear FGFR1 accumulation was accompanied by an inhibition of proliferation of NS/PCs in the subventricular zone (SVZ) and by the generation of new neurons. Neuronal differentiation was observed in different regions of the adult mouse brain, including (a) βIII-Tubulin-expressing cortical neurons, (b) calretinin-expressing hippocampal neurons, and (c) cells in substantia nigra expressing the predopaminergic Nurr1+ phenotype. Furthermore, we showed that in vitro stimulation of neural stem/progenitor cells with α7nAChR agonist directly activated INFS and neuronal-like differentiation. TC-7020 stimulation of the βIII-Tubulin gene was accompanied by increased binding of FGFR1, CREB binding protein, and RNA polymerase II to a Nur77 targeted promoter region. TC-7020 augmented Nur77-dependent activation of nerve growth factor inducible-B protein responsive element, indicating that α7nAChR upregulation of βIII-Tubulin involves neurogenic FGFR1-Nur signaling. The reactivation of INFS and neurogenesis in adult brain by the α7nAChR agonist may offer a new strategy to treat brain injuries, neurodegenerative diseases, and neurodevelopmental diseases.
authors.affiliation: Department of Pathology and Anatomical Sciences, State University of New York at Buffalo, Buffalo, New York, USA.
authors.forename: Sridhar T
authors.initials: ST
authors.lastname: Narla
authors.forename: Ilona
authors.initials: I
authors.lastname: Klejbor
authors.forename: Barbara
authors.initials: B
authors.lastname: Birkaya
authors.forename: Yu-Wei
authors.initials: YW
authors.lastname: Lee
authors.forename: Janusz
authors.initials: J
authors.lastname: Morys
authors.forename: Ewa K
authors.initials: EK
authors.lastname: Stachowiak
authors.forename: Dorota
authors.initials: D
authors.lastname: Prokop
authors.forename: Merouane
authors.initials: M
authors.lastname: Bencherif
authors.forename: Michal K
authors.initials: MK
authors.lastname: Stachowiak
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055495:Neurogenesis / Q000502:physiology*; D018722:Nicotinic Agonists / Q000378:metabolism / Q000494:pharmacology*; D011812:Quinuclidines / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013876:Thiophenes / Q000494:pharmacology; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C573434:5-methyl-N-(2-(pyridin-3-ylmethyl)-1-azabicyclo(2.2.2)oct-3-yl)thiophene-2-carboxamide; C579166:Chrna7 protein, mouse; D018722:Nicotinic Agonists; D011812:Quinuclidines; D011978:Receptors, Nicotinic; D013876:Thiophenes; D064569:alpha7 Nicotinic Acetylcholine Receptor; C496349:Fgfr1 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1
keywords: Adult stem cells; Cell biology; Neural differentiation; Neural stem cell; Nucleus; Signal transduction