Integrative nuclear FGFR1 signaling (INFS) - A common mechanism for ontogenic gene regulation by retinoid and orphan nuclear receptors
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Ontogeny requires coordinated regulation of multigene programs by a plethora of extracellular and intracellular signals, allowing stem cells or stem-like cells to transit from the self-renewal to the differentiated stage. A novel universal gene regulating mechanism, feed forward and gate model has been proposed for Fibroblast Growth Factor Receptor-1 (FGFR1), where FGFR1 modulates the extra/intracellular signals that activate transcription, namely Integrative Nuclear FGFR1 Signaling (INFS). Studies in our and other laboratories have shown that upon stimulation of diverse neurotransmitter, hormonal or growth factor receptors, nuclear FGFR1, which is released from the nuclear matrix or comes from the cytoplasm via importin-β-mediated nuclear translocation, would participate into the regulation of gene transcription and cell differentiation of neural progenitors and other stem-like cells. Nuclear FGFR1 activates transcription in cooperation with CREB binding protein (CBP) and Ribosomal S6 Kinase 1 (RSK1) through a process that involves a direct interaction of FGFR1 with those proteins. FGFR1 was shown to colocalize with the sites of RNA synthesis and associate together with CBP and RSK1 with the promoters of FGFR1 activated genes. As shown with the fgf-2 and th target genes, nuclear FGFR1 activates transcription by recruiting RNA polymerase II and inducing the remodeling of chromatin. Nuclear FGFR1 constitutes a common gene transducer without which many surface receptors and their signaling pathways fail to activate transcription and differentiation of "stem-like" cells. This modulating function would allow FGFR1 to regulate multiple genes and thereby control cell growth and differentiation. Retinoid receptors and NR4A orphan receptors (Nur) are separate classes of ontogenic regulators which contain dual functions, serving both as sequence specific transcription factors (ssTF) and nuclear receptors but do not act via signaling cascades. The pleiotropic developmental effects of retinoids are mediated by retinoic acid receptors (RAR) and retinoid X receptors (RXR), which regulate transcriptional activity as homo/heterodimers by binding retinoic acid responsive elements (RAREs). NR4A nuclear orphan receptors, comprised of Nur77 (NGFI-B), Nurr1 and NOR-1, also function as ssTF at NGFI-B response elements (NBREs) and Nur-responsive elements (NuREs) for the expression of various genes within multiple signaling pathways. My investigation describes how the developmental gene regulating functions of retinoid receptors and NR4A orphan receptor subfamilies are mediated in direct cooperation with FGFR1 and the INFS. The thesis contains two sections. In the first section, I will investigate the role of INFS in RA-induced neuronal differentiation of mouse embryonic stem cells (mESCs). My results clearly show that nuclear FGFR1 interacts with and augments the transcriptional function of retinoid receptors and NR4A orphan receptors on target binding motifs related to, or containing the canonical, RARE, NBRE, or NurRE during RA-mediated neuronal differentiation of mESCs. In the second part, the importance of nuclear FGFR1 will also be demonstrated in NGF-induced PC12 cell differentiation, further supporting our main axis that nuclear as a "universal" gene regulating mediator that directs cell differentiation. In total, this body of work will add to the growing body of evidence that nuclear FGFR1 serves as a universal "feed-forward-and-gate" signaling module that controls cell self-renewal, and differentiation. The notable integrative function of INFS now expands to include retinoid and orphan nuclear receptors.