Global developmental gene programing in embryonic stem cells involves the nuclear form of Fibroblast Growth Factor Receptor 1
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An animal starts its life as a single cell--a fertilized egg. During embryonic development, this single cell divides repeatedly to produce hundreds of different cell-types in a final arrangement of remarkable complexity and accuracy. Complete development of an organism is controlled by four critical processes, including cell proliferation, cell migration, cell interaction and cell differentiation. Key players involved in these four processes include the FGFs and FGFRs, which together comprise a large family of signaling molecules critical for various aspects of embryogenesis, morphogenesis and organogenesis. However, up to this point, many of these biological functions have been attributed to the "canonical" FGF-signaling signaling pathway, in which an FGF ligand acts on the extracellular surface by targeting membrane bound FGFRs, whose activation further triggers intracellular signaling cascades within the cytosol and associated gene transcription within the nucleus. Using genome-wide sequencing and loss and gain of function experiments this study presents a mechanism that relies upon global and direct gene regulation by the nuclear form of FGFR1, ensuring that pluripotent embryonic stem cells differentiate into neuronal cells in response to Retinoic Acid. Nuclear FGFR1 (nFGFR1), both alone and with its partner nuclear receptors RXR and Nur77, targets thousands of differentially regulated genes and controls the expression of pluripotency, homeobox, neuronal and mesodermal genes. Many of these nFGFR1-targeted genes can be organized into developmental pathways represented by Wnt/β-catenin, CREB, Tumor Protein 53 and Bone Morphogenic Protein signaling pathways, pluirpotency, neuroectodermal and mesodermal programming networks, and axonal growth and synaptic plasticity pathways. In association with direct gene targeting, nFGFR1 binds to consensus sequences of transcription factors known to engage CBP, a common coregulator of transcription and established binding partner of nFGFR1. Hence, this investigation demonstrates a potential role for nuclear FGFR1 as a global genomic programmer of cellular, neural and muscle development.