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.
Mesh Terms:
Cells, Cultured, Cytoskeleton, Embryo, Mammalian, Enzyme Activation, Extracellular Matrix Proteins, Fibroblast Growth Factor 2, Gonadotropin-Releasing Hormone, Heparan Sulfate Proteoglycans, Heparitin Sulfate, Humans, Immunohistochemistry, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Nerve Tissue Proteins, Neurites, Neurons, Olfactory Pathways, Protein Isoforms, Receptor Protein-Tyrosine Kinases, Receptor, Fibroblast Growth Factor, Type 1, Receptors, Fibroblast Growth Factor, Signal Transduction, cdc42 GTP-Binding Protein, p38 Mitogen-Activated Protein Kinases, rac1 GTP-Binding Protein
Cells, Cultured, Cytoskeleton, Embryo, Mammalian, Enzyme Activation, Extracellular Matrix Proteins, Fibroblast Growth Factor 2, Gonadotropin-Releasing Hormone, Heparan Sulfate Proteoglycans, Heparitin Sulfate, Humans, Immunohistochemistry, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Nerve Tissue Proteins, Neurites, Neurons, Olfactory Pathways, Protein Isoforms, Receptor Protein-Tyrosine Kinases, Receptor, Fibroblast Growth Factor, Type 1, Receptors, Fibroblast Growth Factor, Signal Transduction, cdc42 GTP-Binding Protein, p38 Mitogen-Activated Protein Kinases, rac1 GTP-Binding Protein
J. Neurosci.
Date: Nov. 17, 2004
PubMed ID: 15548653
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