FGFs and their high-affinity receptors (FGFRs) play key roles in development, tissue repair, and disease. Because FGFRs bind overlapping sets of ligands, their individual functions cannot be determined using ligand stimulation. Here, we generated a light-activated FGFR2 variant (OptoR2) to selectively activate signaling by the major FGFR in keratinocytes. Illumination of OptoR2-expressing HEK 293T cells activated FGFR signaling with remarkable temporal precision and promoted cell migration and proliferation. In murine and human keratinocytes, OptoR2 activation rapidly induced the classical FGFR signaling pathways and expression of FGF target genes. Surprisingly, multi-level counter-regulation occurred in keratinocytes in vitro and in transgenic mice in vivo, including OptoR2 down-regulation and loss of responsiveness to light activation. These results demonstrate unexpected cell type-specific limitations of optogenetic FGFRs in long-term in vitro and in vivo settings and highlight the complex consequences of transferring optogenetic cell signaling tools into their relevant cellular contexts.

中文翻译：

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体外和小鼠角质形成细胞中光激活 FGF 受体的急性和慢性影响。

FGFs 及其高亲和力受体 (FGFRs) 在发育、组织修复和疾病中发挥关键作用。因为 FGFRs 结合重叠的配体组，它们的个别功能不能使用配体刺激来确定。在这里，我们生成了一种光激活的 FGFR2 变体 (OptoR2)，以选择性地激活角质形成细胞中主要 FGFR 的信号传导。光照表达 OptoR2 的 HEK 293T 细胞以显着的时间精度激活 FGFR 信号，并促进细胞迁移和增殖。在小鼠和人类角质形成细胞中，OptoR2 激活迅速诱导经典的 FGFR 信号通路和 FGF 靶基因的表达。令人惊讶的是，体外角质形成细胞和体内转基因小鼠中发生了多级反调节，包括 OptoR2 下调和对光激活的反应性丧失。