Journal
JOURNAL OF NEUROSCIENCE
Volume 24, Issue 46, Pages 10384-10392Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3400-04.2004
Keywords
FGFR1; GnRH; anosmin-1; heparan sulfate proteoglycans; Kallmann's syndrome; MAPKs
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Funding
- Medical Research Council [G9826762, G9900837] Funding Source: Medline
- Wellcome Trust Funding Source: Medline
- MRC [G9900837, G9826762] Funding Source: UKRI
- Medical Research Council [G9900837, G9826762] Funding Source: researchfish
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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.
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