Yap and its subcellular localization have distinct compartment-specific roles in the developing lung
Yap and its subcellular localization have distinct compartment-specific roles in the developing lung
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DOI：
10.1242/dev.175810
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发表时间：
2019-05-01
期刊：
影响因子：
4.6
通讯作者：
Cardoso, Wellington V.
中科院分区：
文献类型：
--
作者：
van Soldt, Benjamin J.;Qian, Jun;Cardoso, Wellington V.
尽管 Hippo-yes 相关蛋白 (Yap) 通路与肺发育有关，但 Yap 及其核细胞质穿梭在发育中的气道和肺泡室中的具体作用仍然难以捉摸。此外，表达研究的相互矛盾的结果以及 Yap 和 Hippo 激酶无效突变体的肺表型差异引起了对发育中肺中 Yap 亚细胞定位的动力学和意义的争议。在这里，我们发现 Yap 缺陷肺的异常形态发生是由于发育事件的破坏（特别是远端上皮祖细胞）造成的。我们还表明，核 Yap 的激活足以满足拯救这些肺部异常的 Yap 要求。值得注意的是，我们发现 Yap 核细胞质穿梭对于上皮祖细胞的分支形态发生和囊化来说在很大程度上是可有可无的。然而，如果在气道中保持转录活性，核 Yap 会深刻改变近端-远端特性并停止上皮分化。总而言之，这些观察结果为了解 Hippo-Yap 信号在产前肺部的至关重要性提供了新的见解。
Although the Hippo-yes-associated protein (Yap) pathway has been implicated in lung development, the specific roles for Yap and its nucleocytoplasmic shuttling in the developing airway and alveolar compartments remain elusive. Moreover, conflicting results from expression studies and differences in the lung phenotypes of Yap and Hippo kinase null mutants caused controversy over the dynamics and significance of Yap subcellular localization in the developing lung. Here, we show that the aberrant morphogenesis of Yap-deficient lungs results from the disruption of developmental events specifically in distal epithelial progenitors. We also show that activation of nuclear Yap is enough to fulfill the Yap requirements to rescue abnormalities in these lungs. Remarkably, we found that Yap nucleocytoplasmic shuttling is largely dispensable in epithelial progenitors for both branching morphogenesis and sacculation. However, if maintained transcriptionally active in airways, nuclear Yap profoundly alters proximal-distal identity and halts epithelial differentiation. Taken together, these observations provide novel insights into the crucial importance of Hippo-Yap signaling in the lung prenatally.