title: Anosmin-1 modulates fibroblast growth factor receptor 1 signaling in human gonadotropin-releasing hormone olfactory neuroblasts through a heparan sulfate-dependent mechanism.
abstract: Defects of either anosmin-1 or fibroblast growth factor receptor 1 (FGFR1) are known to underlie hereditary Kallmann's syndrome (KS), a human disorder of olfactory and gonadotropin-releasing hormone (GnRH) neuronal ontogeny. Here, we report a functional interaction between anosmin-1 and the FGFR1-FGF2-heparan sulfate complex, leading to amplified responses in the FGFR1 signaling pathway. In human embryonic GnRH olfactory neuroblasts, wild-type anosmin-1, but not proteins with loss-of-function KS mutations, induces neurite outgrowth and cytoskeletal rearrangements through FGFR1-dependent mechanisms involving p42/44 and p38 mitogen-activated protein kinases and Cdc42/Rac1 activation. Furthermore, anosmin-1 enhances FGF2 signaling specifically through FGFR1 IIIc in heterologous BaF3 lymphoid cells in a heparan sulfate-dependent manner. Our study provides compelling evidence for anosmin-1 as an isoform-specific co-ligand modulator of FGFR signaling that amplifies and specifies FGFR1 signaling responses during human nervous system development and defines a mechanism underlying the link between autosomal and X-linked KS.
authors.affiliation: Centre for Neuroendocrinology, Royal Free and University College Medical School, London NW3 2PF, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: González-Martínez
authors.forename: Soo-Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Youli
authors.initials: Y
authors.lastname: Hu
authors.forename: Scott
authors.initials: S
authors.lastname: Guimond
authors.forename: Jonathan
authors.initials: J
authors.lastname: Schofield
authors.forename: Paul
authors.initials: P
authors.lastname: Winyard
authors.forename: Gabriella Barbara
authors.initials: GB
authors.lastname: Vannelli
authors.forename: Jeremy
authors.initials: J
authors.lastname: Turnbull
authors.forename: Pierre-Marc
authors.initials: PM
authors.lastname: Bouloux
mesh_terms: D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism / Q000648:ultrastructure; D004622:Embryo, Mammalian / Q000378:metabolism; D004789:Enzyme Activation; D016326:Extracellular Matrix Proteins / Q000378:metabolism / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000502:physiology; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D019812:Heparan Sulfate Proteoglycans / Q000502:physiology; D006497:Heparan Sulfate / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000502:physiology*; D016501:Neurites / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D009833:Olfactory Pathways / Q000166:cytology* / Q000196:embryology; D020033:Protein Isoforms / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D016326:Extracellular Matrix Proteins; D016222:Fibroblast Growth Factor 2; D007987:Gonadotropin-Releasing Hormone; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor; D020764:cdc42 GTP-Binding Protein; D048051:p38 Mitogen-Activated Protein Kinases; D020830:rac1 GTP-Binding Protein; C076266:ANOS1 protein, human; C496348:FGFR1 protein, human