Hyperactive Wnt signaling changes the developmental potential of embryonic lung endoderm.
Hyperactive Wnt signaling changes the developmental potential of embryonic lung endoderm.
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作者：
Okubo T;Hogan BL
在许多模型系统中的研究已经表明，通过Wnt家族配体下游途径的经典信号传导可以调节器官发生中的多个步骤，包括细胞增殖、分化和谱系特化。此外，果蝇成虫盘细胞中Wnt家族成员Wingless的错误表达可导致祖细胞从一个谱系到另一个谱系的转决定。Wnt信号传导途径的β-连环蛋白组分的条件性缺失表明Wnt信号传导在小鼠肺内胚层发育中的作用。然而，包括转录因子Lef 1在内的这一途径的全部效应尚未被探索。为了探索这个问题，我们在转基因胚胎中表达了一种组成型活性β-catenin-Lef 1融合蛋白，该蛋白使用来自表面活性蛋白C基因的肺内胚层特异性启动子。转基因肺外观正常，但内部含有高度增殖的立方上皮，缺乏完全分化的肺细胞类型。出乎意料的是，微阵列分析和原位杂交揭示了一个马赛克的细胞表达标记基因的肠潘氏和杯状细胞和其他非肺分泌细胞类型的特征。此外，有很强的异位表达的基因，如Cdx 1和Atoh 1，通常调节肠道发育和早期分配的细胞肠分泌谱系。我们的研究结果表明，在表达肺特异性基因的肺祖细胞中，过度活跃的Wnt信号传导可以诱导谱系定型和肠细胞类型生成的戏剧性转变。我们讨论了我们的研究结果的相关性，在人类肠上皮化生的病理条件知之甚少。
Studies in many model systems have shown that canonical signaling through the pathway downstream of ligands of the Wnt family can regulate multiple steps in organogenesis, including cell proliferation, differentiation, and lineage specification. In addition, misexpression of the Wnt-family member Wingless in Drosophila imaginal disc cells can lead to transdetermination of progenitors from one lineage to another. Conditional deletion of the β-catenin component of the Wnt signaling pathway has indicated a role for Wnt signaling in mouse lung endoderm development. The full range of effects of this pathway, which includes the transcription factor Lef1, has not been explored, however. To explore this issue, we expressed a constitutively active β-catenin-Lef1 fusion protein in transgenic embryos using a lung-endoderm-specific promoter from the surfactant protein C gene. Transgenic lungs appeared grossly normal, but internally they contained highly proliferative, cuboidal epithelium lacking fully differentiated lung cell types. Unexpectedly, microarray analysis and in situ hybridization revealed a mosaic of cells expressing marker genes characteristic of intestinal Paneth and goblet cells and other non-lung secretory cell types. In addition, there was strong ectopic expression of genes such as Cdx1 and Atoh1 that normally regulate gut development and early allocation of cells to intestinal secretory lineages. Our results show that hyperactive Wnt signaling in lung progenitors expressing a lung-specific gene can induce a dramatic switch in lineage commitment and the generation of intestinal cell types. We discuss the relevance of our findings to the poorly understood pathological condition of intestinal metaplasia in humans.