Anosmin-1 Modulates Fibroblast Growth Factor Receptor 1 Signaling in Human Gonadotropin-Releasing Hormone Olfactory Neuroblasts through a Heparan Sulfate-Dependent Mechanism

• Published in: The Journal of neuroscience 2004-11, Vol.24 (46), p.10384-10392
• Main Authors: Gonzalez-Martinez, David, Kim, Soo-Hyun, Hu, Youli, Guimond, Scott, Schofield, Jonathan, Winyard, Paul, Vannelli, Gabriella Barbara, Turnbull, Jeremy, Bouloux, Pierre-Marc
• Format: Article
• Language: English
• Subjects: cdc42 GTP-Binding Protein - metabolism; Cells, Cultured; Cellular/Molecular; Cytoskeleton - metabolism; Cytoskeleton - ultrastructure; Embryo, Mammalian - metabolism; Enzyme Activation; Extracellular Matrix Proteins - metabolism; Extracellular Matrix Proteins - physiology; Fibroblast Growth Factor 2 - physiology; Gonadotropin-Releasing Hormone - metabolism; Heparan Sulfate Proteoglycans - physiology; Heparitin Sulfate - physiology; Humans; Immunohistochemistry; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Nerve Tissue Proteins - metabolism; Nerve Tissue Proteins - physiology; Neurites - physiology; Neurons - metabolism; Neurons - physiology; Olfactory Pathways - cytology; Olfactory Pathways - embryology; p38 Mitogen-Activated Protein Kinases - metabolism; Protein Isoforms - metabolism; rac1 GTP-Binding Protein - metabolism; Receptor Protein-Tyrosine Kinases - metabolism; Receptor Protein-Tyrosine Kinases - physiology; Receptor, Fibroblast Growth Factor, Type 1; Receptors, Fibroblast Growth Factor - metabolism; Receptors, Fibroblast Growth Factor - physiology; Signal Transduction
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.3400-04.2004

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.