Epithelial heparan sulfate regulates Sonic Hedgehog signaling in lung development.
Epithelial heparan sulfate regulates Sonic Hedgehog signaling in lung development.
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上皮硫酸乙酰肝素调节肺部发育中的 Sonic Hedgehog 信号传导
DOI：
10.1371/journal.pgen.1006992
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发表时间：
2017-08
期刊：
影响因子：
4.5
通讯作者：
Lin X
中科院分区：
文献类型：
--
作者：
He H;Huang M;Sun S;Wu Y;Lin X
哺乳动物肺的树状结构是由分支形态发生产生的，这是一个由许多因素精确调节的反复过程。细胞表面和细胞外基质(ECM)分子如何调控这一过程仍然知之甚少。在此，我们发现上皮型硫酸乙酰肝素合成酶Ext1的缺失导致了分支尖端的扩张和分支数量的减少，这与几种间质发育缺陷有关。我们进一步证明，在Ext1突变肺中，Fgf10的表达扩大，成纤维细胞生长因子信号活性增加，这表明这是一种细胞非自治机制。与此一致，我们观察到负责抑制Fgf10表达的SHH信号水平降低。此外，在突变的肺中重新激活SHH信号可以挽救尖端扩张表型，并减弱成纤维细胞生长因子信号。重要的是，SHH信号活性的降低似乎不是由于Shh表达减少或蛋白质稳定性降低所致；相反，在Ext1突变的上皮细胞和周围的野生型间充质细胞中，生物活性形式的SHH蛋白都减少了。总之，我们的研究强调了上皮性HS是决定SHH信号的关键角色，SHH信号对肺形态发生至关重要。
The tree-like structure of the mammalian lung is generated from branching morphogenesis, a reiterative process that is precisely regulated by numerous factors. How the cell surface and extra cellular matrix (ECM) molecules regulate this process is still poorly understood. Herein, we show that epithelial deletion of Heparan Sulfate (HS) synthetase Ext1 resulted in expanded branching tips and reduced branching number, associated with several mesenchymal developmental defects. We further demonstrate an expanded Fgf10 expression and increased FGF signaling activity in Ext1 mutant lungs, suggesting a cell non-autonomous mechanism. Consistent with this, we observed reduced levels of SHH signaling which is responsible for suppressing Fgf10 expression. Moreover, reactivating SHH signaling in mutant lungs rescued the tip dilation phenotype and attenuated FGF signaling. Importantly, the reduced SHH signaling activity did not appear to be caused by decreased Shh expression or protein stability; instead, biologically active form of SHH proteins were reduced in both the Ext1 mutant epithelium and surrounding wild type mesenchymal cells. Together, our study highlights the epithelial HS as a key player for dictating SHH signaling critical for lung morphogenesis.
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