Kawahira Hiroshi, Scheel David W, Smith Stuart B, German Michael S, Hebrok Matthias
Diabetes Center, Department of Medicine, University of California, San Francisco, CA 94143, USA.
Dev Biol. 2005 Apr 1;280(1):111-21. doi: 10.1016/j.ydbio.2005.01.008.
Embryonic Hedgehog signaling is essential for proper tissue morphogenesis and organ formation along the developing gastrointestinal tract. Hedgehog ligands are expressed throughout the endodermal epithelium at early embryonic stages but excluded from the region that will form the pancreas. Ectopic activation of Hedgehog signaling at the onset of pancreas development has been shown to inhibit organ morphogenesis. In contrast, Hedgehog signaling components are found within pancreatic tissue during subsequent stages of development as well as in the mature organ, indicating that a certain level of pathway activation is required for normal organ development and function. Here, we ectopically activate the Hedgehog pathway midway through pancreas development via expression of either Sonic (Shh) or Indian Hedgehog (Ihh) under control of the human Pax4-promoter. Similar pancreatic defects are observed in both Pax4-Shh and Pax4-Ihh transgenic lines, suggesting that regulation of the overall level of Hedgehog activity is critical for proper pancreas development. We also show that Hedgehog signaling controls mesenchymal vs. epithelial tissue differentiation and that pathway activation impairs formation of epithelial progenitors. Thus, tight control of Hedgehog pathway activity throughout embryonic development ensures proper pancreas organogenesis.
胚胎期的刺猬信号通路对于沿发育中的胃肠道进行正常的组织形态发生和器官形成至关重要。刺猬信号配体在胚胎早期阶段的整个内胚层上皮中表达，但在将形成胰腺的区域中被排除。已表明在胰腺发育开始时刺猬信号通路的异位激活会抑制器官形态发生。相反，在发育的后续阶段以及成熟器官中，在胰腺组织内发现了刺猬信号通路成分，这表明正常器官发育和功能需要一定水平的信号通路激活。在此，我们通过在人Pax4启动子的控制下表达音猬因子（Shh）或印度刺猬因子（Ihh），在胰腺发育中期异位激活刺猬信号通路。在Pax4-Shh和Pax4-Ihh转基因系中均观察到类似的胰腺缺陷，这表明刺猬信号活性的总体水平调节对于胰腺的正常发育至关重要。我们还表明，刺猬信号通路控制间充质与上皮组织的分化，并且信号通路激活会损害上皮祖细胞的形成。因此，在整个胚胎发育过程中严格控制刺猬信号通路活性可确保胰腺正常器官发生。
