Involvement of Sonic hedgehog (Shh) in mouse embryonic lung growth and morphogenesis.
Involvement of Sonic hedgehog (Shh) in mouse embryonic lung growth and morphogenesis.
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发表时间：
1997
期刊：
影响因子：
4.6
通讯作者：
S. Bellusci;Y. Furuta;M. Rush;R. Henderson;G. Winnier;B. Hogan
中科院分区：
文献类型：
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作者：
S. Bellusci;Y. Furuta;M. Rush;R. Henderson;G. Winnier;B. Hogan
胚胎肺的分支形态发生需要上皮和间充质之间的相互作用。以前，我们报告说，音刺猬（Shh）转录本存在于上皮细胞的发育小鼠肺，最高水平的顶芽。在这里，我们报告说，转录的小鼠补丁（Ptc），同源的果蝇基因编码一个假定的跨膜蛋白所需的刺猬信号，表达在高水平的间充质邻近的端芽。为了研究SHH在肺发育中的功能，使用表面活性剂蛋白-C（SP-C）-增强子/启动子在整个远端上皮中过表达Shh。从约16.5 dpc开始，当Shh和Ptc RNA水平正常均下降时，与正常肺相比，该处理导致转基因肺中间质间充质与上皮小管的比率增加。转基因新生小鼠出生后很快死亡。光镜和电镜下肺组织学分析显示间充质丰富，无典型肺泡。体内BrdU标记表明，Shh过表达导致在16.5和17.5 dpc时间充质和上皮细胞增殖增加。然而，CC-10和SP-C表达的分析揭示了在近端和远端上皮细胞的分化中没有显著抑制。还检查了可能由SHH调节的基因的表达。在转基因肺和对照肺之间，在Bmp 4、Wnt 2和Fgf 7 RNA的水平或分布中均未观察到差异。相比之下，Ptc在转基因肺中明显上调。因此，这些结果确立了SHH在肺形态发生中的作用，并表明SHH在体内正常调节肺间充质细胞增殖。
Branching morphogenesis of the embryonic lung requires interactions between the epithelium and the mesenchyme. Previously, we reported that Sonic hedgehog (Shh) transcripts are present in the epithelium of the developing mouse lung, with highest levels in the terminal buds. Here, we report that transcripts of mouse patched (Ptc), the homologue of a Drosophila gene encoding a putative transmembrane protein required for hedgehog signaling, are expressed at high levels in the mesenchyme adjacent to the end buds. To investigate the function of SHH in lung development, Shh was overexpressed throughout the distal epithelium, using the surfactant protein-C (SP-C)-enhancer/promoter. Beginning around 16.5 dpc, when Shh and Ptc RNA levels are normally both declining, this treatment caused an increase in the ratio of interstitial mesenchyme to epithelial tubules in transgenic compared to normal lungs. Transgenic newborn mice die soon after birth. Histological analysis of the lungs at the light and electron microscope level shows an abundance of mesenchyme and the absence of typical alveoli. In vivo BrdU labeling indicates that Shh overexpression results in increased mesenchymal and epithelial cell proliferation at 16.5 and 17.5 dpc. However, analysis of CC-10 and SP-C expression reveals no significant inhibition in the differentiation of proximal and distal epithelial cells. The expression of genes potentially regulated by SHH was also examined. No difference could be observed between transgenic and control lungs in either the level or distribution of Bmp4, Wnt2 and Fgf7 RNA. By contrast, Ptc is clearly upregulated in the transgenic lung. These results thus establish a role for SHH in lung morphogenesis, and suggest that SHH normally regulates lung mesenchymal cell proliferation in vivo.