A requirement for hedgehog signaling in thyroid hormone-induced postembryonic intestinal remodeling.
A requirement for hedgehog signaling in thyroid hormone-induced postembryonic intestinal remodeling.
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DOI：
10.1186/s13578-015-0004-3
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发表时间：
2015
影响因子：
7.5
通讯作者：
Shi YB
中科院分区：
文献类型：
--
作者：
Wen L;Hasebe T;Miller TC;Ishizuya-Oka A;Shi YB
长期以来，两栖动物变态过程中的肠道重塑一直被研究为脊椎动物成体器官形成的模型，特别是成体器官特异性干细胞的形成。像变态过程中的所有其他过程一样，这一过程由甲状腺激素(T3)控制，甲状腺激素通过与T3受体(TRs)结合来影响靶基因的转录调节，从而影响细胞的命运和行为。早期的研究表明，在发育中的成体干细胞中，T3诱导了Sonic Hedgehog(Shh)，Shh受体和其他下游成分存在于结缔组织中，在肠道重塑的高潮时，肌肉中存在较低水平的Shh。然而，还没有活体研究来研究成体细胞产生的Shh是否可以调节结缔组织以促进肠道成熟。我们已经通过用Shh抑制剂环丙胺治疗蝌蚪来解决这个问题。我们发现，环多巴胺而不是结构相关的化学物质托马替丁抑制Shh反应基因BMP4、SNAI2和Twist1的表达。更重要的是，我们发现，在变态的高峰期，环丙胺降低了发育中的成体干细胞以及其他肠道组织中细胞的增殖，导致变态结束时肠的延迟/不完全重塑。我们进一步发现，SNAI2和Twist1在肠道变态过程中都强烈上调，并且它们的表达仅限于结缔组织。我们的结果表明，Shh确实向结缔组织发出信号，通过它可以促进成人干细胞的增殖和促进成人肠道的形成。
Intestinal remodeling during amphibian metamorphosis has long been studied as a model for the formation of the adult organs in vertebrates, especially the formation of adult organ-specific stem cells. Like all other processes during metamorphosis, this process is controlled by thyroid hormone (T3), which affects cell fate and behavior through transcriptional regulation of target genes by binding to T3 receptors (TRs). Earlier studies have shown that Sonic hedgehog (Shh) is induced by T3 in the developing adult stem cells and that the Shh receptor and other downstream components are present in the connective tissue and at lower levels in the muscles at the climax of intestinal remodeling. However, no in vivo studies have carried out to investigate whether Shh produced in the adult cells can regulate the connective tissue to promote intestinal maturation. We have addressed this issue by treating tadpoles with Shh inhibitor cyclopamine. We showed that cyclopamine but not the structurally related chemical tomatidine inhibited the expression of Shh response genes BMP4, Snai2, and Twist1. More importantly, we showed that cyclopamine reduced the cell proliferation of both the developing adult stem cells as well as cells in the other intestinal tissues at the climax of metamorphosis, leading to delayed/incomplete remodeling of the intestine at the end of metamorphosis. We further revealed that both Snai2 and Twist1 were strongly upregulated during metamorphosis in the intestine and their expression was restricted to the connective tissue. Our results suggest that Shh indeed signals the connective tissue whereby it can increase adult stem cell proliferation and promote formation of the adult intestine.
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影响因子：
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