Abstract
BackgroundIntestinal 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.ResultsWe 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.ConclusionsOur results suggest that Shh indeed signals the connective tissue whereby it can increase adult stem cell proliferation and promote formation of the adult intestine.
Highlights
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
Inhibition of hedgehog (Shh) signaling by cyclopamine suppresses intestinal remodeling during Xenopus laevis metamorphosis To investigate the role of endogenous Sonic hedgehog (Shh) signaling during metamorphosis, we treated tadpoles at stage 58, early climax of metamorphosis when upregulation of endogenous Shh begins [36,45], with two structurally related chemicals
When vehicle-treated control tadpoles reached the end of metamorphosis, the animals were sacrificed for analysis
Summary
Inhibition of hedgehog (Shh) signaling by cyclopamine suppresses intestinal remodeling during Xenopus laevis metamorphosis To investigate the role of endogenous Shh signaling during metamorphosis, we treated tadpoles at stage 58, early climax of metamorphosis when upregulation of endogenous Shh begins [36,45], with two structurally related chemicals. All other members of the Shh signaling pathway, including Shh receptor Patched and downstream transcription factors, are all strongly upregulated in the connective tissue at the climax of intestinal metamorphosis when stem cell formation and proliferation take place [44]. Our studies here showed that two other Shh targets, Snai and Twist, likewise, expressed exclusively in the connective tissue at the climax of metamorphosis These results suggest that exogenous Shh enhances cell proliferation in the intestinal organ cultures mainly by signaling the connective tissue. It would be interesting to determine whether there is a similar requirement for Shh for the formation and proliferation of the adult intestinal stem cells in mammals
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