Department of Surgery, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California.
Department of Allergy, Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, People's Republic of China.
Am J Physiol Lung Cell Mol Physiol. 2021 Jun 1;320(6):L1158-L1168. doi: 10.1152/ajplung.00299.2020. Epub 2021 Apr 21.
The TGF-β signaling pathway plays a pivotal role in controlling organogenesis during fetal development. Although the role of TGF-β signaling in promoting lung alveolar epithelial growth has been determined, mesenchymal TGF-β signaling in regulating lung development has not been studied in vivo due to a lack of genetic tools for specifically manipulating gene expression in lung mesenchymal cells. Therefore, the integral roles of TGF-β signaling in regulating lung development and congenital lung diseases are not completely understood. Using a lung enhancer-driven Tet-On inducible Cre transgenic mouse system, we have developed a mouse model in which lung mesenchyme-specific deletion of TGF-β receptor 2 gene ( is achieved. Reduced airway branching accompanied by defective airway smooth muscle growth and later peripheral cystic lesions occurred when lung mesenchymal was deleted from to , resulting in postnatal death due to respiratory insufficiency. Although cell proliferation in both lung epithelium and mesenchyme was reduced, epithelial differentiation was not significantly affected. Tgfbr2 downstream Smad-independent ERK1/2 may mediate these mesenchymal effects of TGF-β signaling through the GSK3β-β-catenin-Wnt canonical pathway in fetal mouse lung. Our study suggests that Tgfbr2-mediated TGF-β signaling in prenatal lung mesenchyme is essential for lung development and maturation, and defective TGF-β signaling in lung mesenchyme may be related to abnormal airway branching morphogenesis and congenital airway cystic lesions.
TGF-β 信号通路在控制胎儿发育过程中的器官发生中起着关键作用。尽管已经确定 TGF-β 信号在促进肺肺泡上皮生长中的作用，但由于缺乏专门用于在肺间质细胞中操纵基因表达的遗传工具，因此尚未在体内研究间质 TGF-β 信号在调节肺发育中的作用。因此，TGF-β 信号在调节肺发育和先天性肺疾病中的整体作用尚不完全清楚。使用肺增强子驱动的 Tet-On 诱导型 Cre 转基因小鼠系统，我们开发了一种小鼠模型，其中肺间质特异性缺失 TGF-β 受体 2 基因（ ）。当从肺上皮细胞到气道平滑肌的肺间质缺失时，气道分支减少伴随着气道平滑肌生长缺陷和随后的外周囊性病变，导致由于呼吸功能不全而导致出生后死亡。尽管肺上皮细胞和间质中的细胞增殖减少，但上皮细胞分化没有受到明显影响。Tgfbr2 下游的 Smad 非依赖性 ERK1/2 可能通过 GSK3β-β-catenin-Wnt 经典途径在胎鼠肺中介导 TGF-β 信号的这些间质效应。我们的研究表明，产前肺间质中 Tgfbr2 介导的 TGF-β 信号对于肺发育和成熟至关重要，肺间质中缺陷的 TGF-β 信号可能与异常气道分支形态发生和先天性气道囊性病变有关。
