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The adult mammalian intestine has long been used as a model to study adult stem cell function and tissue renewal as the intestinal epithelium is constantly undergoing self-renewal throughout adult life. This is accomplished through the proliferation and subsequent differentiation of the adult stem cells located in the crypt. The development of this self-renewal system is, however, poorly understood. A number of studies suggest that the formation/maturation of the adult intestine is conserved in vertebrates and depends on endogenous thyroid hormone (T3). In amphibians such as Xenopus laevis, the process takes place during metamorphosis, which is totally dependent upon T3 and resembles postembryonic development in mammals when T3 levels are also high. During metamorphosis, the larval epithelial cells in the tadpoleintestine undergo apoptosis and concurrently, adult epithelial stem/progenitor cells are formed de novo, which subsequently lead to the formation of a trough-crest axis of the epithelial fold in the frog, resembling the crypt-villus axis in the adult mammalian intestine. Here we will review some recent molecular and genetic studies that support the conservation of the development of the adult intestinal stem cells in vertebrates. We will discuss the mechanisms by which T3 regulates this process via its nuclear receptors.
Fig 1. Intestinal remodeling during Xenopus laevis metamorphosis as a model to study adult organ-specific stem cell development in vertebrates. In premetamorphic tadpoles at stage 51, the intestine has only a single fold, the typhlosole, and is structurally similar to the mammalian embryonic intestine. At the metamorphic climax around stage 61, the larval epithelial cells begin to undergo apoptosis, as indicated by the open circles. Concurrently, the proliferating adult progenitor/stem cells are developed de novo from larval epithelial cells through dedifferentiation, as indicated by black dots. By the end of metamorphosis at stage 66, the newly differentiated adult epithelial cells form a multiply folded epithelium, similar to mammalian adult intestines.
Fig 2. The adult intestinal stem cell marker gene LGR5 is upregulated at the climax of intestinal metamorphosis. Cross-sections of the intestine at premetamorphic stage 54 (A, A'), metamorphic climax stage 62 (B, B'), and the end of metamorphosis (stage 66) (C, C') were analyzed by in situ hybridization for LGR5 expression. Arrows indicate the cells expressing LGR5 (A'-C'). Higher magnification of boxed areas in (A)-(C) are shown in (A')-(C'). AE: adult epithelial progenitor/stem cells, CT: connective tissue, LE: larval epithelial cell, Lu: lumen, M: muscle layer, Ty: typhlosole. Scale bars are 100 µm (A-C) and 20 µm (A'-C'), respectively. Based on 14.
Fig 3. A model for gene regulation by TR. T3 functions by regulating gene transcription through T3 receptors (TRs). In the absence of T3 (as in premetamorphic tadpole), TR forms heterodimers with RXR (9-cis retinoic acid receptor) and the heterodimer binds to the T3 response elements (TREs) in the target genes to repress their expression by recruiting corepressor complexes containing histone deacetylases. When T3 is present, the corepressor complexes are released and the liganded TR/RXR recruits coactivator complexes containing histone acetyltransferases and histone methyltransferases such as PRMT1 (protein arginine methyltransferase 1). The coactivator complexes will modify histones or cause the removal of nucleosomes, leading to the activation of gene expression. Based on 55.
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