Endodermal Wnt signaling is required for tracheal cartilage formation.
Endodermal Wnt signaling is required for tracheal cartilage formation.
复制标题
DOI：
10.1016/j.ydbio.2015.06.009
复制
发表时间：
2015-09-01
影响因子：
2.7
通讯作者：
Sinner D
中科院分区：
文献类型：
--
作者：
Snowball J;Ambalavanan M;Whitsett J;Sinner D
气管支气管软化症是一种常见的先天性缺陷，其中气管和支气管的壁缺乏支撑气道所需的足够软骨。使用ShhCre小鼠在胚胎内胚层中缺失Wls（一种介导Wnt配体分泌的货物受体）抑制气管-支气管软骨环的形成。气管间充质的正常背腹型消失。通过Acta 2染色鉴定的平滑肌细胞异常地位于气管的腹侧间充质中，通常位于软骨祖细胞中Sox 9表达的区域。Axin 2 LacZ报告基因显示，Wlsf/f;ShhCre/+胚胎气管间质中Wnt/β-catenin活性降低。在Wlsf/f;ShhCre/+气管组织中，成软骨细胞增殖减少，平滑肌细胞增殖增加。Tbx 4，Tbx 5，Msx 1和Msx 2的表达，已知介导软骨和肌肉图案，减少在气管间充质的Wlsf/f;ShhCre/+胚胎。离体研究表明，在间充质凝聚形成之前，由发育中的气管上皮表达的Wnt 7 b和Wnt 5a以及活性Wnt/β-连环蛋白信号传导是气管软骨形成所需的。总之，由气管上皮产生的Wnt配体通过调节适当的气管软骨和平滑肌分化所需的基因表达和细胞增殖来形成气管间充质。
Tracheobronchomalacia is a common congenital defect in which the walls of the trachea and bronchi lack of adequate cartilage required for support of the airways. Deletion of Wls, a cargo receptor mediating Wnt ligand secretion, in the embryonic endoderm using ShhCre mice inhibited formation of tracheal-bronchial cartilaginous rings. The normal dorsal-ventral patterning of tracheal mesenchyme was lost. Smooth muscle cells, identified by Acta2 staining, were aberrantly located in ventral mesenchyme of the trachea, normally the region of Sox9 expression in cartilage progenitors. Wnt/β-catenin activity, indicated by Axin2 LacZ reporter, was decreased in tracheal mesenchyme of Wlsf/f;ShhCre/+ embryos. Proliferation of chondroblasts was decreased and reciprocally, proliferation of smooth muscle cells was increased in Wlsf/f;ShhCre/+ tracheal tissue. Expression of Tbx4, Tbx5, Msx1 and Msx2, known to mediate cartilage and muscle patterning, were decreased in tracheal mesenchyme of Wlsf/f;ShhCre/+ embryos. Ex vivo studies demonstrated that Wnt7b and Wnt5a, expressed by the epithelium of developing trachea, and active Wnt/β-catenin signaling are required for tracheal chondrogenesis before formation of mesenchymal condensations. In conclusion, Wnt ligands produced by the tracheal epithelium pattern the tracheal mesenchyme via modulation of gene expression and cell proliferation required for proper tracheal cartilage and smooth muscle differentiation.