Distinct fibroblast growth factor (FGF)/FGF receptor signaling pairs initiate diverse cellular responses in the oligodendrocyte lineage
Distinct fibroblast growth factor (FGF)/FGF receptor signaling pairs initiate diverse cellular responses in the oligodendrocyte lineage
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DOI：
10.1523/jneurosci.2120-05.2005
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发表时间：
2005-08-10
影响因子：
5.3
通讯作者：
Bansal, R
中科院分区：
文献类型：
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作者：
Fortin, D;Rom, E;Bansal, R
成纤维细胞生长因子 (FGF) 与许多细胞过程有关，包括增殖、迁移、分化和存活。 FGF-2 是 22 个成员家族中的原型配体，可激活所有四种酪氨酸激酶 FGF 受体 (FGFR1-FGFR4)，而其他成员则表现出更高程度的选择性。少突胶质细胞 (OL) 是中枢神经系统中产生髓磷脂的细胞，在其发育的各个阶段都受到 FGF-2 的高度影响。然而，其他 FGF 及其同源受体如何协调 OL 的发育基本上尚不清楚。通过结合特异性 FGF 配体和受体阻断抗体，我们现在发现 FGF-8 和 FGF-17 靶向 OL 祖细胞，通过激活 FGFR3 抑制其终末分化，而 FGF-9 特异性靶向分化的 OL，通过 FGFR2 信号传导触发过程生长的增加； FGF-18 通过激活 FGFR2 和 FGFR3 来靶向 OL 祖细胞和 OL。当 OL 祖细胞分化为成熟 OL 时，这些事件与 FGF 受体表达从 FGFR3 到 FGFR2 的变化高度相关。此外，我们证明，虽然 FGF-2 激活 FGFR1 会导致 OL 祖细胞增殖，但它会对分化的 OL 产生有害影响（即异常重新进入细胞周期和髓磷脂蛋白下调并导致髓磷脂膜丢失）。这些数据表明，配体可用性与 FGF 受体表达的变化相结合，产生配体-受体信号复合物的变化，这对正常 OL 发育和潜在 OL/髓磷脂发病机制的调节至关重要。
Fibroblast growth factors (FGFs) have been implicated in numerous cellular processes, including proliferation, migration, differentiation, and survival. Whereas FGF-2, the prototypic ligand in a family of 22 members, activates all four tyrosine kinase FGF receptors (FGFR1-FGFR4), other members demonstrate a higher degree of selectivity. Oligodendrocytes (OLs), the myelin-producing cells of the CNS, are highly influenced by FGF-2 at all stages of their development. However, how other FGFs and their cognate receptors orchestrate the development of OLs is essentially undefined. Using a combination of specific FGF ligands and receptor blocking antibodies, we now show that FGF-8 and FGF-17 target OL progenitors, inhibiting their terminal differentiation via the activation of FGFR3, whereas FGF-9 specifically targets differentiated OLs, triggering increases in process growth via FGFR2 signaling; FGF-18 targets both OL progenitors and OLs via activation of both FGFR2 and FGFR3. These events are highly correlated with changes in FGF receptor expression from FGFR3 to FGFR2 as OL progenitors differentiate into mature OLs. In addition, we demonstrate that, although activation of FGFR1 by FGF-2 leads to proliferation of OL progenitors, it produces deleterious effects on differentiated OLs (i.e., aberrant reentry into cell cycle and down-regulation of myelin proteins with a loss of myelin membrane). These data suggest that ligand availability, coupled with changes in FGF receptor expression, yield a changing repertoire of ligand-receptor signaling complexes that contribute critically to the regulation of both normal OL development and potential OL/myelin pathogenesis.