Dicer function is essential for lung epithelium morphogenesis
Dicer function is essential for lung epithelium morphogenesis
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DOI：
10.1073/pnas.0510839103
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发表时间：
2006-02-14
影响因子：
11.1
通讯作者：
Sun, X
中科院分区：
文献类型：
--
作者：
Harris, KS;Zhang, Z;Sun, X
DICER是一种关键酶，它将微小RNA和小干扰RNA前体加工成它们的短成熟形式，使其能够调节基因表达。小鼠基因组中仅存在一个Dicer基因，且它在发育中的组织中广泛表达。Dicer基因缺失的突变体在原肠胚形成之前死亡。因此，为了研究Dicer在肺形成后期事件中的功能，我们使用Dicer条件性等位基因和音猬因子（cre）（Shh（cre））等位基因在小鼠肺上皮细胞中使其失活。这些突变体肺中的分支停滞，尽管上皮生长在与正常样本相比扩张的远端区域仍在继续。这些缺陷导致突变体肺中出现几个大的上皮囊袋，而非正常肺中存在的众多细小分支。重要的是，在观察到上皮细胞死亡增加之前，初始表型就已明显，这使我们提出Dicer在调节肺上皮形态发生中具有特定作用，与其在细胞存活中的作用无关。此外，我们发现参与肺发育的关键基因Fgf10的表达在Dicer突变体肺的间充质中上调且范围扩大。先前的研究支持这样一种假设，即FGF10在肺间充质离散部位的精确定位作为上皮分支向外生长的化学引诱物。异常的Fgf10表达可能导致Dicer形态缺陷。然而，DICER在上皮细胞中发挥作用以影响间充质中Fgf10表达的机制仍然未知。
DICER is a key enzyme that processes microRNA and small interfering RNA precursors into their short mature forms, enabling them to regulate gene expression. Only a single Dicer gene exists in the mouse genome, and it is broadly expressed in developing tissues. Dicer-null mutants die before gastrulation. Therefore, to study Dicer function in the later event of lung formation, we inactivated it in the mouse lung epithelium using a Dicer conditional allele and the Sonic Hedgehog(cre) (Shh(cre)) allele. Branching arrests in these mutant lungs, although epithelial growth continues in distal domains that are expanded compared with normal samples. These defects result in a few large epithelial pouches in the mutant lung instead of numerous fine branches present in a normal lung. Significantly, the initial phenotypes are apparent before an increase in epithelial cell death is observed, leading us to propose that Dicer plays a specific role in regulating lung epithelial morphogenesis independent of its requirement in cell survival. In addition, we found that the expression of Fgf10, a key gene involved in lung development, is up-regulated and expanded in the mesenchyme of Dicer mutant lungs. Previous studies support the hypothesis that precise localization of FGF10 in discrete sites of the lung mesenchyme serves as a chemoattractant for the outgrowth of epithelial branches. The aberrant Fgf10 expression may contribute to the Dicer morphological defects. However, the mechanism by which DICER functions in the epithelium to influence Fgf10 expression in the mesenchyme remains unknown.