title: A novel nuclear FGF Receptor-1 partnership with retinoid and Nur receptors during developmental gene programming of embryonic stem cells.
abstract: FGF Receptor-1 (FGFR1), a membrane-targeted protein, is also involved in independent direct nuclear signaling. We show that nuclear accumulation of FGFR1 is a common response to retinoic acid (RA) in pluripotent embryonic stem cells (ESC) and neural progenitors and is both necessary and sufficient for neuronal-like differentiation and accompanying neuritic outgrowth. Dominant negative nuclear FGFR1, which lacks the tyrosine kinase domain, prevents RA-induced differentiation while full-length nuclear FGFR1 elicits differentiation in the absence of RA. Immunoprecipitation and GST assays demonstrate that FGFR1 interacts with RXR, RAR and their Nur77 and Nurr1 partners. Conditions that promote these interactions decrease the mobility of nuclear FGFR1 and RXR in live cells. RXR and FGFR1 co-associate with 5'-Fluorouridine-labeled transcription sites and with RA Responsive Elements (RARE). RA activation of neuronal (tyrosine hydroxylase) and neurogenic (fgf-2 and fgfr1) genes is accompanied by increased FGFR1, Nur, and histone H3.3 binding to their regulatory sequences. Reporter-gene assays show synergistic activations of RARE, NBRE, and NurRE by FGFR1, RAR/RXR, and Nurs. As shown for mESC differentiation, FGFR1 mediates gene activation by RA and augments transcription in the absence of RA. Cooperation of FGFR1 with RXR/RAR and Nurs at targeted genomic sequences offers a new mechanism in developmental gene regulation.
authors.affiliation: Molecular and Structural Neurobiology and Gene Therapy Program, Department of Pathology and Anatomical Sciences, State University of New York, Buffalo, New York 14214, USA.
authors.forename: Yu-Wei
authors.initials: YW
authors.lastname: Lee
authors.forename: Christopher
authors.initials: C
authors.lastname: Terranova
authors.forename: Barbara
authors.initials: B
authors.lastname: Birkaya
authors.forename: Sridhar
authors.initials: S
authors.lastname: Narla
authors.forename: Daniel
authors.initials: D
authors.lastname: Kehoe
authors.forename: Abhirath
authors.initials: A
authors.lastname: Parikh
authors.forename: Shuo
authors.initials: S
authors.lastname: Dong
authors.forename: Andreas
authors.initials: A
authors.lastname: Ratzka
authors.forename: Hella
authors.initials: H
authors.lastname: Brinkmann
authors.forename: John M
authors.initials: JM
authors.lastname: Aletta
authors.forename: Emmanuel S
authors.initials: ES
authors.lastname: Tzanakakis
authors.forename: Ewa K
authors.initials: EK
authors.lastname: Stachowiak
authors.forename: Peter
authors.initials: P
authors.lastname: Claus
authors.forename: Michal K
authors.initials: MK
authors.lastname: Stachowiak
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D036681:Fluorescence Recovery After Photobleaching; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*
chemical_list: D057093:Orphan Nuclear Receptors; D018168:Receptors, Retinoic Acid; D051496:Receptor, Fibroblast Growth Factor, Type 1