Fgfr1 regulates development through the combinatorial use of signaling proteins.
Fgfr1 regulates development through the combinatorial use of signaling proteins.
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DOI：
10.1101/gad.264994.115
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发表时间：
2015-09-01
影响因子：
10.5
通讯作者：
Soriano P
中科院分区：
文献类型：
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作者：
Brewer JR;Molotkov A;Mazot P;Hoch RV;Soriano P
Brewer等人设计了一系列敲入点突变的等位基因，旨在单独和联合破坏Fgfr 1信号传导功能。他们发现，除了Frs 2，Crk蛋白和Plcγ也有助于Erk 1/2激活。所有已知的信号传导功能的破坏减少了Erk 1/2和Plcγ的激活，但没有重现着床期Fgfr 1-null表型。成纤维细胞生长因子（Fgf）信号传导控制在发育和疾病中重要的多个过程。许多证据表明，通过Frs 2诱导的Erk 1/2信号传导是Fgf受体（Fgfrs）下游的主要效应途径，但这些受体也可以通过其他机制发出信号。为了探索小鼠中Fgfrs下游全范围信号传导的功能意义，我们设计了一系列敲入点突变的等位基因，旨在单独和组合破坏Fgfr 1信号传导功能。对每个突变体的分析表明，Frs 2与Fgfr 1的结合在发育中具有最多效的功能，而且该受体在体内添加使用多种蛋白质。除了Frs 2，Crk蛋白和Plcγ也有助于Erk 1/2激活，影响轴伸长和颅面和肢体发育，并为附加信号需求提供生化机制。所有已知的信号传导功能的破坏减少了Erk 1/2和Plcγ的激活，但没有重现着床期Fgfr 1-null表型。这表明Erk 1/2-非依赖性信号传导途径对体内FGF信号传导具有重要的功能。
Brewer et al. engineered an allelic series of knock-in point mutations designed to disrupt Fgfr1 signaling functions individually and in combination. They found that, in addition to Frs2, Crk proteins and Plcγ also contribute to Erk1/2 activation. Disruption of all known signaling functions diminished Erk1/2 and Plcγ activation but did not recapitulate the peri-implantation Fgfr1-null phenotype. Fibroblast growth factor (Fgf) signaling governs multiple processes important in development and disease. Many lines of evidence have implicated Erk1/2 signaling induced through Frs2 as the predominant effector pathway downstream from Fgf receptors (Fgfrs), but these receptors can also signal through other mechanisms. To explore the functional significance of the full range of signaling downstream from Fgfrs in mice, we engineered an allelic series of knock-in point mutations designed to disrupt Fgfr1 signaling functions individually and in combination. Analysis of each mutant indicates that Frs2 binding to Fgfr1 has the most pleiotropic functions in development but also that the receptor uses multiple proteins additively in vivo. In addition to Frs2, Crk proteins and Plcγ also contribute to Erk1/2 activation, affecting axis elongation and craniofacial and limb development and providing a biochemical mechanism for additive signaling requirements. Disruption of all known signaling functions diminished Erk1/2 and Plcγ activation but did not recapitulate the peri-implantation Fgfr1-null phenotype. This suggests that Erk1/2-independent signaling pathways are functionally important for Fgf signaling in vivo.