Activation of Developmental Nuclear Fibroblast Growth Factor Receptor 1 Signaling and Neurogenesis in Adult Brain by α7 Nicotinic Receptor Agonist

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 alpha 7 nicotinic acetylcholine receptors (alpha 7nAChRs) 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) beta III-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 alpha 7nAChR agonist directly activated INFS and neuronal-like differentiation. TC-7020 stimulation of the beta III-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 alpha 7nAChR upregulation of beta III-Tubulin involves neurogenic FGFR1-Nur signaling. The reactivation of INFS and neurogenesis in adult brain by the alpha 7nAChR agonist may offer a new strategy to treat brain injuries, neurodegenerative diseases, and neurodevelopmental diseases.