Department of Neuroscience, University of Connecticut Medical School, Farmington, Connecticut 06030, USA.
J Neurosci. 2011 Mar 30;31(13):5055-66. doi: 10.1523/JNEUROSCI.4800-10.2011.
Fibroblast growth factors (FGFs) comprise a family of developmental regulators implicated in a wide variety of neurological functions. FGF receptors 1, 2, and 3 (Fgfrs) are expressed in the embryonic forebrain, including regions overlapping with ventral sites of oligodendrocyte progenitor (OLP) generation. Although FGF signaling is known to influence the proliferation of OLPs in vitro, functions of different Fgfrs in vivo are lacking. Here, we examined single and double mutants with conditional disruption of Fgfrs, specifically in the embryonic forebrain, to investigate the effect of FGFs on the generation and proliferation of OLPs in vivo. FGF signaling, through cooperation between Fgfr1 and Fgfr2 but not Fgfr3, is required for the initial generation of OLPs in the mouse ventral forebrain, with Fgfr1 being a stronger inducer than Fgfr2. In cultures derived from embryonic mutant forebrains or from normal forebrains grown in the presence of Fgfr inhibitor, a strong attenuation of OLP generation was observed, supporting the role of FGF signaling in vivo. Contrary to in vitro findings, Fgfr1 and Fgfr2 signaling is not required for the proliferation of OLPs in vivo. Finally, failure of OLP generation in the Fgfr mutants occurred without loss of sonic hedgehog (Shh) signaling; and pharmacological inhibition of either Fgfr or hedgehog signaling in parallel cultures strongly inhibited OLP generation, suggesting that Fgfrs cooperate with Shh to generate OLPs. Overall, our results reveal for the first time an essential role of FGF signaling in vivo, where the three Fgfrs differentially control the normal generation of OLPs from the embryonic ventral forebrain.
成纤维细胞生长因子（FGFs）是一个家族的发育调节剂，涉及多种神经功能。FGF 受体 1、2 和 3（Fgfrs）在胚胎前脑中表达，包括与少突胶质前体细胞（OLP）发生的腹侧部位重叠的区域。尽管已知 FGF 信号在体外影响 OLP 的增殖，但体内不同 Fgfrs 的功能尚不清楚。在这里，我们检查了条件性破坏 Fgfrs 的单突变体和双突变体，特别是在胚胎前脑中，以研究 FGFs 对体内 OLP 发生和增殖的影响。FGF 信号通过 Fgfr1 和 Fgfr2 之间的合作，但不是 Fgfr3，对于小鼠腹侧前脑 OLP 的初始发生是必需的，其中 Fgfr1 是比 Fgfr2 更强的诱导物。在从胚胎突变前脑或在 Fgfr 抑制剂存在下生长的正常前脑中衍生的培养物中，观察到 OLP 发生的强烈衰减，支持 FGF 信号在体内的作用。与体外发现相反，Fgfr1 和 Fgfr2 信号对于体内 OLP 的增殖不是必需的。最后，在 Fgfr 突变体中 OLP 发生的失败没有丧失 sonic hedgehog（Shh）信号；并且平行培养物中 Fgfr 或 hedgehog 信号的药理学抑制强烈抑制 OLP 的发生，表明 Fgfrs 与 Shh 合作产生 OLP。总的来说，我们的结果首次揭示了 FGF 信号在体内的重要作用，其中三个 Fgfrs 以不同的方式控制胚胎腹侧前脑 OLP 的正常发生。
