Murcia-Belmonte Verónica, Medina-Rodríguez Eva M, Bribián Ana, de Castro Fernando, Esteban Pedro F
Grupo de Neurobiología del Desarrollo-GNDe, Hospital Nacional de Parapléjicos, Finca "La Peraleda, s/n, E-45071-Toledo, Spain.
Glia. 2014 Mar;62(3):374-86. doi: 10.1002/glia.22609. Epub 2013 Dec 21.
Signaling through fibroblast growth factor receptors (FGFRs) is essential for many cellular processes including proliferation and migration, as well as differentiation events such as myelination. Anosmin-1 is an extracellular matrix (ECM) glycoprotein that interacts with the fibroblast growth factor receptor 1 (FGFR1) to exert its biological actions through this receptor, although the intracellular pathways underlying anosmin-1 signaling remain largely unknown. This protein is defective in the X-linked form of Kallmann syndrome (KS) and has a prominent role in the migration of neuronal and oligodendroglial precursors. We have shown that anosmin-1 exerts a chemotactic effect via FGFR1 on neuronal precursors from the subventricular zone (SVZ) and the essential role of the ERK1/2 signaling. We report here the positive chemotactic effect of FGF2 and anosmin-1 on rat and mouse postnatal OPCs via FGFR1. The same effect was observed with the truncated N-terminal region of anosmin-1 (A1Nt). The introduction in anosmin-1 of the missense mutation F517L found in patients suffering from KS annulled the chemotactic activity; however, the mutant form carrying the disease-causing mutation E514K also found in KS patients, behaved as the wild-type protein. The chemoattraction exhibited by FGF2 and anosmin-1 on OPCs was blocked by the mitogen-activated protein kinase (MAPK) inhibitor U0126, suggesting that the activation of the ERK1/2 MAPK signaling pathway following interaction with the FGFR1 is necessary for FGF2 and anosmin-1 to exert their chemotactic effect. In fact, both proteins were able to induce the phosphorylation of the ERK1/2 kinases after the activation of the FGFR1 receptor.
通过成纤维细胞生长因子受体（FGFRs）进行的信号传导对于许多细胞过程至关重要，包括增殖和迁移，以及诸如髓鞘形成等分化事件。 anosmin-1是一种细胞外基质（ECM）糖蛋白，它与成纤维细胞生长因子受体1（FGFR1）相互作用，通过该受体发挥其生物学作用，尽管anosmin-1信号传导的细胞内途径在很大程度上仍然未知。 这种蛋白质在X连锁型卡尔曼综合征（KS）中存在缺陷，并且在神经元和少突胶质前体细胞的迁移中起重要作用。 我们已经表明，anosmin-1通过FGFR1对来自脑室下区（SVZ）的神经元前体细胞发挥趋化作用，并且ERK1 / 2信号传导起着至关重要的作用。 我们在此报告FGF2和anosmin-1通过FGFR1对大鼠和小鼠出生后少突胶质前体细胞（OPCs）的正向趋化作用。 在anosmin-1的截短N端区域（A1Nt）中也观察到相同的效果。 在患有KS的患者中发现的错义突变F517L引入anosmin-1中消除了趋化活性； 然而，在KS患者中也发现的携带致病突变E514K的突变形式表现得与野生型蛋白一样。 FGF2和anosmin-1对OPCs表现出的化学吸引作用被丝裂原活化蛋白激酶（MAPK）抑制剂U0126阻断，这表明与FGFR1相互作用后ERK1 / 2 MAPK信号通路的激活是FGF2和anosmin-1发挥其趋化作用所必需的。 事实上，两种蛋白质在FGFR1受体激活后都能够诱导ERK1 / 2激酶的磷酸化。
