Bmp signaling regulates proximal-distal differentiation of endoderm in mouse lung development.
Bmp signaling regulates proximal-distal differentiation of endoderm in mouse lung development.
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发表时间：
1999-09
期刊：
影响因子：
4.6
通讯作者：
Molly Weaver;J. Yingling;N. R. Dunn;S. Bellusci;Brigid L. M. Hogan
中科院分区：
文献类型：
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作者：
Molly Weaver;J. Yingling;N. R. Dunn;S. Bellusci;Brigid L. M. Hogan
在成熟小鼠肺中，近端-远端（P-D）轴由两个不同的上皮亚群描绘：近端细支气管上皮和远端呼吸道上皮。人们对于沿 P-D 轴形成肺部模式的信号分子知之甚少。其中一个候选者是骨形态发生蛋白 4 (Bmp4)，它在生长的肺芽尖端的上皮细胞中以动态模式表达。先前的研究表明，Bmp4 在肺内胚层中过度表达（Bellusci, S.、Henderson, R.、Winnier, G.、Oikawa, T. 和 Hogan, B. L. M. (1996) Development 122, 1693-1702）表明该因子在肺形态发生中发挥重要作用。为了进一步研究这个问题，采用了两种互补的方法来抑制体内 Bmp 信号传导。使用表面活性剂蛋白 C (Sp-C) 启动子/增强子过表达 Bmp 拮抗剂 Xnoggin 和显性失活 Bmp 受体 (dnAlk6)。抑制 Bmp 信号传导会导致远端上皮细胞类型严重减少，同时近端细胞类型同时增加，如标记基因的形态和表达所示，包括近端表达的肝细胞核因子/叉头同源物 4 (Hfh4) 和 Clara 细胞标记 CC10 以及远端标记 Sp-C。此外，电子显微镜显示转基因肺的最外周区域存在纤毛细胞（一种近端细胞类型）。我们提出了一个模型，其中 Bmp4 是控制 P-D 模式的顶端信号中心的一个组成部分。暴露于高水平 Bmp4 的肺周围的内胚层细胞保持或采用远端特征，而接收很少或不接收 Bmp4 信号的细胞启动近端分化程序。
In the mature mouse lung, the proximal-distal (P-D) axis is delineated by two distinct epithelial subpopulations: the proximal bronchiolar epithelium and the distal respiratory epithelium. Little is known about the signaling molecules that pattern the lung along the P-D axis. One candidate is Bone Morphogenetic Protein 4 (Bmp4), which is expressed in a dynamic pattern in the epithelial cells in the tips of growing lung buds. Previous studies in which Bmp4 was overexpressed in the lung endoderm (Bellusci, S., Henderson, R., Winnier, G., Oikawa, T. and Hogan, B. L. M. (1996) Development 122, 1693-1702) suggested that this factor plays an important role in lung morphogenesis. To further investigate this question, two complementary approaches were utilized to inhibit Bmp signaling in vivo. The Bmp antagonist Xnoggin and, independently, a dominant negative Bmp receptor (dnAlk6), were overexpressed using the surfactant protein C (Sp-C) promoter/enhancer. Inhibiting Bmp signaling results in a severe reduction in distal epithelial cell types and a concurrent increase in proximal cell types, as indicated by morphology and expression of marker genes, including the proximally expressed hepatocyte nuclear factor/forkhead homologue 4 (Hfh4) and Clara cell marker CC10, and the distal marker Sp-C. In addition, electron microscopy demonstrates the presence of ciliated cells, a proximal cell type, in the most peripheral regions of the transgenic lungs. We propose a model in which Bmp4 is a component of an apical signaling center controlling P-D patterning. Endodermal cells at the periphery of the lung, which are exposed to high levels of Bmp4, maintain or adopt a distal character, while cells receiving little or no Bmp4 signal initiate a proximal differentiation program.