Developmental stage-specific role of Frs adapters as mediators of FGF receptor signaling in the oligodendrocyte lineage cells.
Developmental stage-specific role of Frs adapters as mediators of FGF receptor signaling in the oligodendrocyte lineage cells.
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作者：
Furusho M;Ishii A;Hebert JM;Bansal R
FGF信号传导对于许多细胞过程是重要的，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-受体1（Fgfr 1）或Fgfr 2的小鼠的研究表明，Fgfr信号首先需要胚胎少突胶质细胞祖细胞（OPC）的规格，然后出生后活跃髓鞘形成过程中髓鞘的生长，但不是OPC增殖，分化，或ensheathment轴突。哪些细胞内信号转导途径被募集到Fgfrs的下游并介导这些不同的发育调节阶段特异性反应仍不清楚。衔接蛋白成纤维细胞生长因子受体底物-2（Frs 2）被认为是Fgfrs的关键直接下游靶标。因此，在这里，我们研究了在少突胶质细胞谱系细胞中的Frs衔接子的体内作用，使用一种新的遗传方法，其中小鼠被改造为破坏Frs 2与Fgfr 1或Fgfr 2的结合，从而特异性地解偶联Frs 2和Fgfr信号。此外，我们使用了Frs 2和Frs 3完全消除的条件突变体。我们发现，Frs 2是所需的规格OPCs在胚胎端脑下游的Fgfr 1。相比之下，Frs 2在很大程度上被用于转导Fgfr 2介导的信号，用于在出生后髓鞘形成期间髓鞘的生长，这意味着Fgfr 2下游的其他适配器可能参与该功能。总之，我们的数据证明了Frs 2在少突胶质细胞系细胞中的发育阶段特异性功能。这种背景下的衔接蛋白的要求，下游的Fgfrs，可以部分解释不同的反应引起的激活Fgfrs在髓鞘形成的不同阶段。
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.
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