Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles, CA 90027, USA.
Dev Biol. 2013 Oct 1;382(1):110-23. doi: 10.1016/j.ydbio.2013.07.019. Epub 2013 Jul 26.
The Eya1 gene encodes a transcriptional co-activator that acts with Six1 to control the development of different organs. However, Six1-Eya1 interactions and functional roles in mesenchymal cell proliferation and differentiation as well as alveolarization during the saccular stage of lung development are still unknown. Herein, we provide the first evidence that Six1 and Eya1 act together to regulate mesenchymal development as well as alveolarization during the saccular phase of lung morphogenesis. Deletion of either or both Six1 and Eya1 genes results in a severe saccular phenotype, including defects of mesenchymal cell development and remodeling of the distal lung septae and arteries. Mutant lung histology at the saccular phase shows mesenchymal and saccular wall thickening, and abnormal proliferation of α-smooth muscle actin-positive cells, as well as increased mesenchymal/fibroblast cell differentiation, which become more sever when deleting both genes. Our study indicates that SHH but not TGF-β signaling pathway is a central mediator for the histologic alterations described in the saccular phenotype of Eya1(-/-) or Six1(-/-) lungs. Indeed, genetic reduction of SHH activity in vivo or inhibition of its activity in vitro substantially rescues lung mesenchymal and alveolar phenotype of mutant mice at the saccular phase. These findings uncover novel functions for Six1-Eya1-SHH pathway during the saccular phase of lung morphogenesis, providing a conceptual framework for future mechanistic and translational studies in this area.
Eya1 基因编码一种转录共激活因子，它与 Six1 一起作用，控制不同器官的发育。然而，Six1-Eya1 相互作用以及在间质细胞增殖和分化以及肺泡形成中的功能作用，在肺发育囊泡期仍然未知。在此，我们首次提供证据表明，Six1 和 Eya1 共同作用，调节肺形态发生囊泡期的间质发育和肺泡形成。Six1 和 Eya1 基因的缺失或两者的缺失都导致严重的囊泡表型，包括间质细胞发育缺陷和远端肺小隔和动脉的重塑。囊泡期的突变肺组织学显示间质和囊泡壁增厚，以及 α-平滑肌肌动蛋白阳性细胞的异常增殖，并且当同时缺失两个基因时，这种异常增殖变得更加严重。我们的研究表明，SHH 而不是 TGF-β 信号通路是 Eya1(-/-)或 Six1(-/-)肺囊泡表型中描述的组织学改变的中心介质。事实上，体内 SHH 活性的遗传降低或体外抑制其活性，可大大挽救囊泡期突变小鼠的肺间质和肺泡表型。这些发现揭示了 Six1-Eya1-SHH 通路在肺形态发生囊泡期的新功能，为该领域的未来机制和转化研究提供了概念框架。
