FGF-Regulated ETV Transcription Factors Control FGF-SHH Feedback Loop in Lung Branching.
FGF-Regulated ETV Transcription Factors Control FGF-SHH Feedback Loop in Lung Branching.
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DOI：
10.1016/j.devcel.2015.10.006
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发表时间：
2015-11-09
影响因子：
11.8
通讯作者：
Sun X
中科院分区：
文献类型：
--
作者：
Herriges JC;Verheyden JM;Zhang Z;Sui P;Zhang Y;Anderson MJ;Swing DA;Zhang Y;Lewandoski M;Sun X
哺乳动物的肺按照很大程度上刻板的分支序列形成了复杂的树状结构。虽然已经确定了一些基因在肺分支中发挥重要作用，但如何协调分支生长和新分支形成之间的选择还没有被阐明。在这里，我们表明，丢失了成纤维细胞生长因子激活的转录因子基因Etw4和ETV5(统称为ETV)，导致了枝尖生长的延长和新枝的形成延迟。出乎意料的是，这种表型更类似于有增加的，而不是减少的成纤维细胞生长因子活性的突变体。事实上，观察到Fgf10表达增加，减少Fgf10的剂量可以减弱ETV突变表型。进一步的证据表明，ETV通过直接促进Shh的表达来抑制Fgf10。Shh反过来抑制局部Fgf10的表达，重定向生长，从而启动新的分支。综上所述，我们的发现确立了ETV是决定分支节奏的FGF-ETV-SHH抑制反馈环路中的关键节点。
The mammalian lung forms its elaborate tree-like structure following a largely stereotypical branching sequence. While a number of genes have been identified to play essential roles in lung branching, what coordinates the choice between branch growth and new branch formation has not been elucidated. Here we show that loss of FGF-activated transcription factor genes, Etv4 and Etv5 (collectively Etv), led to prolonged branch tip growth and delayed new branch formation. Unexpectedly, this phenotype is more similar to mutants with increased, rather than decreased FGF activity. Indeed, an increased Fgf10 expression is observed and reducing Fgf10 dosage can attenuate the Etv mutant phenotype. Further evidence indicates that ETV inhibits Fgf10 via directly promoting Shh expression. SHH in turn inhibits local Fgf10 expression and redirects growth, thereby initiating new branches. Together, our findings establish ETV as a key node in the FGF-ETV-SHH inhibitory feedback loop that dictates the rhythm of branching.