FGF signaling is important for numerous cellular processes and produces diverse cellular responses. Our recent studies using mice conditionally lacking FGF-Receptor-1 (Fgfr1) or Fgfr2 during different stages of myelinogenesis revealed that Fgfr signaling is first required embryonically for the specification of oligodendrocyte progenitors (OPCs) and then later postnatally for the growth of the myelin sheath during active myelination but not for OPC proliferation, differentiation, or ensheathment of axons. What intracellular signal transduction pathways are recruited immediately downstream of Fgfrs and mediate these distinct developmentally regulated stage-specific responses remain unclear. The adapter protein Fibroblast-Growth-Factor-Receptor-Substrate-2 (Frs2) is considered a key immediate downstream target of Fgfrs. Therefore, here, we investigated the in vivo role of Frs adapters in the oligodendrocyte lineage cells, using a novel genetic approach where mice were engineered to disrupt binding of Frs2 to Fgfr1 or Fgfr2, thus specifically uncoupling Frs2 and Fgfr signaling. In addition, we used conditional mutants with complete ablation of Frs2 and Frs3. We found that Frs2 is required for specification of OPCs in the embryonic telencephalon downstream of Fgfr1. In contrast, Frs2 is largely dispensable for transducing Fgfr2-mediated signals for the growth of the myelin sheath during postnatal myelination, implying the potential involvement of other adapters downstream of Fgfr2 for this function. Together, our data demonstrate a developmental stage-specific function of Frs2 in the oligodendrocyte lineage cells. This contextual requirement of adapter proteins, downstream of Fgfrs, could partly explain the distinct responses elicited by the activation of Fgfrs during different stages of myelinogenesis.

中文翻译：

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Frs 接头在少突胶质细胞谱系细胞中作为 FGF 受体信号传导介质的发育阶段特异性作用。

FGF 信号传导对许多细胞过程很重要，并产生不同的细胞反应。我们最近使用在髓鞘形成的不同阶段条件性缺乏 FGF-Receptor-1 (Fgfr1) 或 Fgfr2 的小鼠进行的研究表明，Fgfr 信号首先在胚胎时期被需要用于少突胶质祖细胞 (OPCs) 的规范，然后在出生后用于髓鞘的生长在活跃的髓鞘形成过程中，但不用于 OPC 增殖、分化或轴突的包裹。什么细胞内信号转导途径在 Fgfrs 的下游立即被招募并介导这些不同的发育调节的阶段特异性反应仍不清楚。衔接蛋白 Fibroblast-Growth-Factor-Receptor-Substrate-2 (Frs2) 被认为是 Fgfrs 的关键直接下游目标。因此，在这里，我们研究了 Frs 接头在少突胶质细胞谱系细胞中的体内作用，使用一种新的遗传方法，其中设计小鼠以破坏 Frs2 与 Fgfr1 或 Fgfr2 的结合，从而特异性地解偶联 Frs2 和 Fgfr 信号。此外，我们使用了完全消融 Frs2 和 Frs3 的条件突变体。我们发现 Frs2 是 Fgfr1 下游胚胎端脑中 OPCs 规范所必需的。相比之下，Frs2 在很大程度上可用于在出生后髓鞘形成过程中转导 Fgfr2 介导的髓鞘生长信号，这意味着 Fgfr2 下游的其他适配器可能参与此功能。总之，我们的数据证明了少突胶质细胞谱系中 Frs2 的发育阶段特异性功能。衔接蛋白的这种背景要求，