Anosmin-1 modulates fibroblast growth factor receptor 1 signaling in human gonadotropin-releasing hormone olfactory neuroblasts through a heparan sulfate-dependent mechanism.
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.
González-Martínez
David
D
Centre for Neuroendocrinology, Royal Free and University College Medical School, London NW3 2PF, United Kingdom.
Kim
Soo-Hyun
SH
Hu
Youli
Y
Guimond
Scott
S
Schofield
Jonathan
J
Winyard
Paul
P
Vannelli
Gabriella Barbara
GB
Turnbull
Jeremy
J
Bouloux
Pierre-Marc
PM
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
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