González-Martínez David, Kim Soo-Hyun, Hu Youli, Guimond Scott, Schofield Jonathan, Winyard Paul, Vannelli Gabriella Barbara, Turnbull Jeremy, Bouloux Pierre-Marc
Centre for Neuroendocrinology, Royal Free and University College Medical School, London NW3 2PF, United Kingdom.
J Neurosci. 2004 Nov 17;24(46):10384-92. 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.
已知嗅觉缺失因子1（anosmin-1）或成纤维细胞生长因子受体1（FGFR1）的缺陷是遗传性卡尔曼综合征（KS）的基础，KS是一种嗅觉和促性腺激素释放激素（GnRH）神经元个体发育异常的人类疾病。在此，我们报道了anosmin-1与FGFR1-FGF2-硫酸乙酰肝素复合物之间的功能相互作用，导致FGFR1信号通路中的反应放大。在人类胚胎GnRH嗅觉神经母细胞中，野生型anosmin-1而非具有功能丧失性KS突变的蛋白质，通过涉及p42/44和p38丝裂原活化蛋白激酶以及Cdc42/Rac1激活的FGFR1依赖性机制诱导神经突生长和细胞骨架重排。此外，anosmin-1以硫酸乙酰肝素依赖性方式在异源BaF3淋巴细胞中通过FGFR1 IIIc特异性增强FGF2信号。我们的研究提供了令人信服的证据，证明anosmin-1作为FGFR信号的亚型特异性共配体调节剂，在人类神经系统发育过程中放大并确定FGFR1信号反应，并确定了常染色体和X连锁KS之间联系的潜在机制。
