Lats1/2 inactivation reveals Hippo function in alveolar type I cell differentiation during lung transition to air breathing
Lats1/2 inactivation reveals Hippo function in alveolar type I cell differentiation during lung transition to air breathing
复制标题
DOI：
10.1242/dev.163105
复制
发表时间：
2018-11-01
期刊：
影响因子：
4.6
通讯作者：
Sun, Xin
中科院分区：
文献类型：
--
作者：
Nantie, Leah B.;Young, Randee E.;Sun, Xin
肺在出生时生长到最佳大小是由反复的呼吸道分支以及随后的肺泡细胞类型的分化和扩张推动的。这种精心设计的生长是如何与胸部的约束相协调的，目前还知之甚少。在这里，我们研究了河马信号，一个控制器官大小的基本途径，在小鼠肺发育中的作用。出乎意料的是，我们发现河马激酶基因Lats1和Lats2(Lats1/2)上皮细胞的缺失导致肺大小显著减小，这是因为分支形态发生提前停止。伴随这种生长缺陷的是上皮细胞极性、细胞分裂平面和细胞外基质沉积的异常，以及作为终末分化指标的1型肺泡上皮细胞(AEC1s)的早熟和表达增加。在下游转录效应因子YAP的组成核形式过表达的转基因小鼠中，也观察到AEC1的增加。相反，YAP和TAZ的缺失导致了AEC1的减少，这表明典型的河马信号通路对于驱动AEC1的命运是充分和必要的。这些发现共同揭示了河马-LATS-YAP信号在发育中的小鼠肺中的独特作用。
Lung growth to its optimal size at birth is driven by reiterative airway branching followed by differentiation and expansion of alveolar cell types. How this elaborate growth is coordinated with the constraint of the chest is poorly understood. Here, we investigate the role of Hippo signaling, a cardinal pathway in organ size control, in mouse lung development. Unexpectedly, we found that epithelial loss of the Hippo kinase genes Lats1 and Lats2 (Lats1/2) leads to a striking reduction of lung size owing to an early arrest of branching morphogenesis. This growth defect is accompanied by abnormalities in epithelial cell polarity, cell division plane and extracellular matrix deposition, as well as precocious and increased expression of markers for type 1 alveolar epithelial cells (AEC1s), an indicator of terminal differentiation. Increased AEC1s were also observed in transgenic mice with overexpression of a constitutive nuclear form of downstream transcriptional effector YAP. Conversely, loss of Yap and Taz led to decreased AEC1s, demonstrating that the canonical Hippo signaling pathway is both sufficient and necessary to drive AEC1 fate. These findings together reveal unique roles of Hippo-LATS-YAP signaling in the developing mouse lung.