Activation of Developmental Nuclear Fibroblast Growth Factor Receptor 1 Signaling and Neurogenesis in Adult Brain by α7 Nicotinic Receptor Agonist. (6th September 2013)

• Record Type: Journal Article
• Authors: Narla, Sridhar T.; Klejbor, Ilona; Birkaya, Barbara; Lee, Yu-Wei; Morys, Janusz; Stachowiak, Ewa K.; Prokop, Dorota; Bencherif, Merouane; Stachowiak, Michal K.
• Is Part Of: Stem cells translational medicine. Volume 2:Number 10(2013)
• Page Start: 776
• Page End: 788
• Publication Date: 2013-09-06
• Subjects: Adult stem cells -- Cell biology -- Neural differentiation -- Neural stem cell -- Nucleus -- Signal transduction; Stem cells -- Periodicals; Regenerative medicine -- Periodicals; Periodicals; 616.0277405
• DOI: 10.5966/sctm.2012-0103
• Languages: English
• ISSNs: 2157-6564

Abstract

Abstract : This study found that targeting the α7 nicotinic acetylcholine receptors (α7nAChRs) with a specific TC‐7020 agonist led to a robust accumulation of endogenous fibroblast growth factor receptor 1 (FGFR1) in the cell nucleus and neuronal differentiation of neural progenitor cells in brain cortex, hippocampus, and substantia nigra. The reactivation of integrative nuclear FGFR1 signaling and neurogenesis in adult brain by the α7nAChR agonist offers a new strategy to treat brain injuries, neurodegenerative diseases, and neurodevelopmental diseases. 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.