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Activation of developmental nuclear fibroblast growth factor receptor 1 signaling and neurogenesis in adult brain by ?7 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 ?7 nicotinic acetylcholine receptors (?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) ?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 ?7nAChR agonist directly activated INFS and neuronal-like differentiation. TC-7020 stimulation of the ?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 ?7nAChR upregulation of ?III-Tubulin involves neurogenic FGFR1-Nur signaling. The reactivation of INFS and neurogenesis in adult brain by the ?7nAChR agonist may offer a new strategy to treat brain injuries, neurodegenerative diseases, and neurodevelopmental diseases.

SUBMITTER: Narla ST

PROVIDER: S-EPMC3785262 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Activation of developmental nuclear fibroblast growth factor receptor 1 signaling and neurogenesis in adult brain by α7 nicotinic receptor agonist.

Narla Sridhar T ST Klejbor Ilona I Birkaya Barbara B Lee Yu-Wei YW Morys Janusz J Stachowiak Ewa K EK Prokop Dorota D Bencherif Merouane M Stachowiak Michal K MK

Stem cells translational medicine 20130906 10

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 ...[more]

PMID: 24014683

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Project description:We constructed and characterized a series of nicotinic receptor mutants with a cysteine substituted for one of the amino acid residues in the alpha-subunit between positions 183 and 198. This region of the receptor is known to participate in agonist binding and channel activation. The goal of this 'cysteine scanning mutagenesis' is to introduce the reactivity of a free thiol group into functionally important protein domains; modification of the introduced cysteines can then be used to probe the structure and function of the targeted region. Mutants were examined by coexpression with the beta-, gamma- and delta-subunits in Xenopus oocytes using two-microelectrode voltage clamp recording. Twelve of fourteen mutants expressed receptors with properties comparable with the wild-type, including sensitivity to reduction by dithiothreitol (DTT). This indicates that introduction of an additional cysteine within this region of the receptor did not interfere with formation of the native disulphide between alpha Cys-192 and alpha Cys-193. Only one mutation, alpha Y198C, caused dramatic changes in the EC50 for acetylcholine (ACh) and in the sensitivity to DTT. We then examined the effects of the thiol modification and found two mutants, alpha H186C and alpha V188C, that showed significant decreases in responsiveness to ACh after exposure to methylmethanethiosulphonate (MMTS). Dose-response measurements show that exposure of alpha H186C mutants to MMTS causes a shift in apparent agonist affinity without changing the peak response, and this is not reversible by DTT. In contrast, the MMTS-treated alpha V188C mutants show changes in both apparent affinity and peak response which are readily reversed by DTT. Together, our data show that these two nearby residues occupy markedly different environments relative to the contact points for ACh. They also demonstrate that cysteine-substitution mutagenesis can be successfully applied to protein domains that include functionally important disulphides.

Dataset Information

Activation of developmental nuclear fibroblast growth factor receptor 1 signaling and neurogenesis in adult brain by ?7 nicotinic receptor agonist.

Publications

Activation of developmental nuclear fibroblast growth factor receptor 1 signaling and neurogenesis in adult brain by α7 nicotinic receptor agonist.

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