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The Journal of Neuroscience, November 17, 2004, 24(46):10384-10392; doi:10.1523/JNEUROSCI.3400-04.2004
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Cellular/Molecular
Anosmin-1 Modulates Fibroblast Growth Factor Receptor 1 Signaling in Human Gonadotropin-Releasing Hormone Olfactory Neuroblasts through a Heparan Sulfate-Dependent Mechanism
David González-Martínez,1 Soo-Hyun Kim,1 Youli Hu,1 Scott Guimond,2 Jonathan Schofield,1 Paul Winyard,3 Gabriella Barbara Vannelli,4 Jeremy Turnbull,2 andPierre-Marc Bouloux1 1Centre for Neuroendocrinology, Royal Free and University College Medical School, London NW3 2PF, United Kingdom, 2School of Biological Sciences, University of Liverpool, Liverpool L69 7ZB, United Kingdom, 3Nephro-Urology Unit, Institute of Child Health, London WC1N 1EH, United Kingdom, and 4Department of Human Anatomy, University of Florence, School of Medicine, I-50134 Florence, Italy
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.
Key words: FGFR1; GnRH; anosmin-1; heparan sulfate proteoglycans; Kallmann's syndrome; MAPKs
Received July 1, 2004; revised October 1, 2004; accepted October 5, 2004.
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