The importance of endogenous nuclear FGFR1 for neuronal differentiation is underscored by the observation that dominant negative tyrosine kinase deleted nuclear FGFR1 or nuclear/ cytoplasmic FGFR1 prevents NGF-induced neurite outgrowth and transcriptional programming. Conversely, transfection of constitutively active nuclear FGFR1 initiates neurite outgrowth, neurite regeneration and activates transcription in the absence NGF. This demonstrates nuclear accumulation of FGFR1 BAY-60-7550 constitutes a sufficient signal for activation of neuronal genes as well as initiation and maintenance of morphological differentiation. The extent of this differentiation will be investigated further to delineate the associated physiological features. Activation of INFS by transfection of nuclear FGFR1 was shown to induce an exit from the cell cycle, morphological differentiation and the expression of neuron-specific proteins in PC12 cells, human brain- or umbilical cord blood-derived Neural Progenitor Cells, mESC, neoplastic medulloblastoma and neuroblastoma cells. Furthermore, transfection of nuclear FGFR1 or its 23 kDa FGF-2 ligand re-instates neuronogenesis in the adult brain in vivo. Our results are consistent with earlier demonstrations of NGF upregulation of FGFR1 expression and FGFR1 activation in PC12 cells, as well as the inhibition of NGF-induced differentiation by dominant negative FGF receptors. Gene expression is clearly re-ordered during NGF-induced neuronal differentiation and the present investigation demonstrates the involvement of INFS in this aspect of NGF signaling. The gene responsible for the rate-limiting enzyme for catecholamine synthesis, th, is activated by nuclear FGFR1 in cooperation with CBP. Importantly, INFS activation provides a mechanism sufficient to promote Nur77 dependent gene activation in the absence of NGF, similar to what has been observed for PC12 cell morphological differentiation. Therefore, we propose that FGFR1 serves as a cofactor for Nur-mediated gene activation and differentiation. In general, nuclear FGFR1 activation of Nur77 is more pronounced than Nurr1 in PC12 cells, consistent with the model in which Nur77 transduces NGF stimulation. A principal finding of our investigation is the cooperative Ibrutinib function of Nurs and nuclear FGFR1 on genes related to PC12 neuronal differentiation. Both FGFR1 and Nur77/Nurr1 are central nuclear integrators of diverse developmental signals and have been implicated in post-mitotic development. Our previous work has identified the association of FGFR1 with retinoid and orphan Nur nuclear receptors on regulatory regions on th, fgf2 and fgfr1 genes in mESC, and on the th gene in the rat brain. The mechanisms by which nuclear FGFR1 increases Nur transcriptional activity also require further investigation. Through interactions with CBP, FGFR1 may recruit this transcriptional coactivator to Nur-occupied DNA enhancers. Such a mechanism appears to operate during RA-induced gene activation in which coordinated binding of Nur, FGFR1 and CBP to RA-activated genes is observed. Another possible mechanism could involve post-translational modifications of Nurs that may be promoted by FGFR1. Nurs can be regulated by phosphorylation as well by acetylation. For instance, Nurr1 phosphorylation by ERK2 plays an important role in regulating TH expression. A recent report that the acetylation by CBP-related p300, and the HDAC1 partner, increase the stability of Nur77, further suggesting a mechanism by which various factors, including NGF, may control Nur77 turnover and function. Thus, activation of INFS, which leads to the dissociation of an inactive CBP-RSK1 complex and the subsequent activation of CBP and RSK1 by FGFR1, may provide a stimulating effect for Nur-dependent transcriptional activation. Our results provide upstream context for the previously demonstrated essential role of RSK1 in NGF-induced PC12 neuronal differentiation.