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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cells, Cultured
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Cytoskeleton / metabolism
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Cytoskeleton / ultrastructure
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Embryo, Mammalian / metabolism
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Enzyme Activation
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Extracellular Matrix Proteins / metabolism
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Extracellular Matrix Proteins / physiology*
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Fibroblast Growth Factor 2 / physiology
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Gonadotropin-Releasing Hormone / metabolism*
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Heparan Sulfate Proteoglycans / physiology
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Heparitin Sulfate / physiology*
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Humans
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Immunohistochemistry
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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Nerve Tissue Proteins / metabolism
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Nerve Tissue Proteins / physiology*
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Neurites / physiology
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Neurons / metabolism
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Neurons / physiology*
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Olfactory Pathways / cytology*
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Olfactory Pathways / embryology
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Protein Isoforms / metabolism
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Receptor Protein-Tyrosine Kinases / metabolism
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Receptor Protein-Tyrosine Kinases / physiology*
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Receptor, Fibroblast Growth Factor, Type 1
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Receptors, Fibroblast Growth Factor / metabolism
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Receptors, Fibroblast Growth Factor / physiology*
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Signal Transduction
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cdc42 GTP-Binding Protein / metabolism
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p38 Mitogen-Activated Protein Kinases / metabolism
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rac1 GTP-Binding Protein / metabolism
Substances
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ANOS1 protein, human
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Extracellular Matrix Proteins
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Heparan Sulfate Proteoglycans
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Nerve Tissue Proteins
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Protein Isoforms
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Receptors, Fibroblast Growth Factor
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Fibroblast Growth Factor 2
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Gonadotropin-Releasing Hormone
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Heparitin Sulfate
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FGFR1 protein, human
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Receptor Protein-Tyrosine Kinases
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Receptor, Fibroblast Growth Factor, Type 1
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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p38 Mitogen-Activated Protein Kinases
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cdc42 GTP-Binding Protein
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rac1 GTP-Binding Protein