Ustiyan Vladimir, Zhang Yufang, Perl Anne-Karina T, Whitsett Jeffrey A, Kalin Tanya V, Kalinichenko Vladimir V
Division of Pulmonary Biology, Perinatal Institute of Cincinnati Children's Research Foundation, Cincinnati, Ohio.
Division of Developmental Biology, Perinatal Institute of Cincinnati Children's Research Foundation, Cincinnati, Ohio.
Dev Dyn. 2016 May;245(5):590-604. doi: 10.1002/dvdy.24393. Epub 2016 Mar 8.
Lung morphogenesis is regulated by interactions between the canonical Wnt/β-catenin and Kras/ERK/Foxm1 signaling pathways that establish proximal-peripheral patterning of lung tubules. How these interactions influence the development of respiratory epithelial progenitors to acquire airway as compared to alveolar epithelial cell fate is unknown. During branching morphogenesis, SOX9 transcription factor is normally restricted from conducting airway epithelial cells and is highly expressed in peripheral, acinar progenitor cells that serve as precursors of alveolar type 2 (AT2) and AT1 cells as the lung matures.
To identify signaling pathways that determine proximal-peripheral cell fate decisions, we used the SFTPC gene promoter to delete or overexpress key members of Wnt/β-catenin and Kras/ERK/Foxm1 pathways in fetal respiratory epithelial progenitor cells. Activation of β-catenin enhanced SOX9 expression in peripheral epithelial progenitors, whereas deletion of β-catenin inhibited SOX9. Surprisingly, deletion of β-catenin caused accumulation of atypical SOX9-positive basal cells in conducting airways. Inhibition of Wnt/β-catenin signaling by Kras(G12D) or its downstream target Foxm1 stimulated SOX9 expression in basal cells. Genetic inactivation of Foxm1 from Kras(G12D) -expressing epithelial cells prevented the accumulation of SOX9-positive basal cells in developing airways.
Interactions between the Wnt/β-catenin and the Kras/ERK/Foxm1 pathways are essential to restrict SOX9 expression in basal cells. Developmental Dynamics 245:590-604, 2016. © 2016 Wiley Periodicals, Inc.
肺形态发生受经典Wnt/β-连环蛋白和Kras/ERK/Foxm1信号通路之间相互作用的调控，这些信号通路建立了肺小管的近端-外周模式。与肺泡上皮细胞命运相比，这些相互作用如何影响呼吸道上皮祖细胞发育以形成气道尚不清楚。在分支形态发生过程中，SOX9转录因子通常在传导气道上皮细胞中受到限制，而在肺成熟时作为2型肺泡（AT2）和AT1细胞前体的外周腺泡祖细胞中高度表达。
为了确定决定近端-外周细胞命运决定的信号通路，我们使用SFTPC基因启动子在胎儿呼吸道上皮祖细胞中删除或过表达Wnt/β-连环蛋白和Kras/ERK/Foxm1通路的关键成员。β-连环蛋白的激活增强了外周上皮祖细胞中SOX9的表达，而β-连环蛋白的缺失则抑制了SOX9。令人惊讶的是，β-连环蛋白的缺失导致传导气道中出现非典型SOX9阳性基底细胞的积累。Kras（G12D）或其下游靶点Foxm1对Wnt/β-连环蛋白信号的抑制刺激了基底细胞中SOX9的表达。从表达Kras（G12D）的上皮细胞中对Foxm1进行基因失活可防止发育中的气道中SOX9阳性基底细胞的积累。
Wnt/β-连环蛋白和Kras/ERK/Foxm1通路之间的相互作用对于限制基底细胞中SOX9的表达至关重要。《发育动力学》245:590 - 604，2016年。©2016威利期刊公司
