Abstract
Nerve growth factor (NGF) is the founding member of the polypeptide neurotrophin family responsible for neuronal differentiation. To determine whether the effects of NGF rely upon novel Integrative Nuclear FGF Receptor-1 (FGFR1) Signaling (INFS) we utilized the PC12 clonal cell line, a long-standing benchmark model of sympathetic neuronal differentiation. We demonstrate that NGF increases expression of the fgfr1 gene and promotes trafficking of FGFR1 protein from cytoplasm to nucleus by inhibiting FGFR1 nuclear export. Nuclear-targeted dominant negative FGFR1 antagonizes NGF-induced neurite outgrowth, doublecortin (dcx) expression and activation of the tyrosine hydroxylase (th) gene promoter, while active constitutive nuclear FGFR1 mimics the effects of NGF. NGF increases the expression of dcx, th, βIII tubulin, nurr1 and nur77, fgfr1and fibroblast growth factor-2 (fgf-2) genes, while enhancing binding of FGFR1and Nur77/Nurr1 to those genes. NGF activates transcription from isolated NurRE and NBRE motifs. Nuclear FGFR1 transduces NGF activation of the Nur dimer and raises basal activity of the Nur monomer. Cooperation of nuclear FGFR1 with Nur77/Nurr1 in NGF signaling expands the integrative functions of INFS to include NGF, the first discovered pluripotent neurotrophic factor.
Highlights
Neuronal differentiation is fundamentally important for understanding normal human development as well as the implementation of new therapeutic interventions for neurological diseases
Our confocal analyses show small increases of FGF Receptor-1 (FGFR1)-IR nuclear foci after only one hour of Nerve growth factor (NGF) treatment (Fig. S1B supplementary material), indicating an early activation of nuclear FGFR1 trafficking by NGF. This early FGFR1 nuclear accumulation is augmented by Leptomycin B (LMB) (Fig. S1C supplementary material), which blocks CRM1dependent nuclear export of proteins [50,51]
Our results demonstrate that Integrative Nuclear FGFR1 Signaling (INFS) contributes unique and previously unknown requirements to support specific end-points of the NGF mechanism, including gene activation and neurite outgrowth
Summary
Neuronal differentiation is fundamentally important for understanding normal human development as well as the implementation of new therapeutic interventions for neurological diseases. NGF is the founding member of the polypeptide neurotrophin family, activates transmembrane tyrosine kinase receptor TrkA [4] and is responsible for the survival and differentiation of sympathetic and dorsal root ganglion neurons, as well as other cells (neuronal and non-neuronal) in both the central nervous system and the periphery [5]. The PC12 rat adrenal pheochromocytoma cell line is an experimental model system used extensively to study neuronal differentiation and has revealed many aspects of the NGF mechanism of action [6,7]. NGF induces biochemical, electrophysiological and morphological (neurite outgrowth) changes in PC12 cells that recapitulate many features characteristic of differentiated sympathetic neurons [8,9]. Studies on PC12 cells have enabled a quantitative picture of proximal NGF signaling events based on a uniform homogeneous population of cells [10]
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