The fibroblast growth factor (FGF) pathway is a conserved signaling pathway required for embryonic development. Activated FGF receptor 1 (FGFR1) drives multiple intracellular signaling cascade pathways, including ERK/MAPK and PI3K/AKT, collectively termed canonical signaling. However, unlike Fgfr1-null embryos, embryos containing hypomorphic mutations in Fgfr1 lacking the ability to activate canonical downstream signals are still able to develop to birth but exhibit severe defects in all mesodermal-derived tissues. The introduction of an additional signaling mutation further reduces the activity of Fgfr1, leading to earlier lethality, reduced somitogenesis, and more severe changes in transcriptional outputs. Genes involved in migration, ECM interaction, and phosphoinositol signaling were significantly downregulated, proteomic analysis identified changes in interactions with endocytic pathway components, and cells expressing mutant receptors show changes in endocytic trafficking. Together, we identified processes regulating early mesoderm development by mechanisms involving both canonical and noncanonical Fgfr1 pathways, including direct interaction with cell adhesion components and endocytic regulation.

中文翻译：

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多样化的 Fgfr1 信号通路和内吞转运调节中胚层发育


成纤维细胞生长因子 （FGF） 通路是胚胎发育所需的保守信号通路。激活的 FGF 受体 1 （FGFR1） 驱动多个细胞内信号级联通路，包括 ERK/MAPK 和 PI3K/AKT，统称为经典信号转导。然而，与 Fgfr1 缺失的胚胎不同，在 Fgfr1 中包含亚态突变且缺乏激活典型下游信号能力的胚胎仍然能够发育到出生，但在所有中胚层衍生组织中表现出严重的缺陷。引入额外的信号突变进一步降低了 Fgfr1 的活性，导致更早的致死性、减少的体细胞发生和更严重的转录输出变化。参与迁移、ECM 相互作用和磷酸肌醇信号传导的基因显着下调，蛋白质组学分析确定了与内吞途径成分相互作用的变化，表达突变受体的细胞显示内吞运输的变化。我们一起确定了通过涉及经典和非经典 Fgfr1 通路的机制调节早期中胚层发育的过程，包括与细胞粘附成分的直接相互作用和内吞调节。