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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Dicer function is essential for lung epithelium morphogenesis
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Dicer function is essential for lung epithelium morphogenesis

机译：切块机功能对于肺上皮形态发生至关重要

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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.
机译：DICER是一种关键酶，可将microRNA和小的干扰RNA前体加工成短的成熟形式，从而使其能够调节基因表达。小鼠基因组中仅存在一个Dicer基因，并且在发育中的组织中广泛表达。 Dicer-null突变体在消化之前死亡。因此，为了研究在随后的肺形成事件中Dicer的功能，我们使用Dicer条件等位基因和Sonic Hedgehog（cre）（Shh〜（cre））等位基因在小鼠肺上皮中使其失活。尽管上皮细胞的生长在与正常样品相比扩大了的远端区域中继续发生，但这些突变肺中的分支停止。这些缺陷导致突变肺中有一些大的上皮囊，而不是正常肺中存在许多细支。重要的是，在观察到上皮细胞死亡增加之前，初始表型是显而易见的，这使我们提出，Dicer在调节肺上皮形态发生中起特定作用，而与细胞存活的要求无关。此外，我们发现在Dicer突变型肺的间充质中，Fgf10（参与肺发育的关键基因）的表达上调并扩展。先前的研究支持以下假说：FGF10在肺间充质离散部位的精确定位可作为上皮分支向外生长的趋化因子。 Fgf10异常表达可能有助于切丁机的形态缺陷。但是，DICER在上皮细胞中发挥功能来影响间充质中Fgf10表达的机制仍然未知。

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