Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Int J Biol Sci
2012 Jan 01;88:1217-24. doi: 10.7150/ijbs.5109.
Show Gene links
Show Anatomy links
Thyroid hormone regulation of adult intestinal stem cell development: mechanisms and evolutionary conservations.
Sun G
,
Shi YB
.
???displayArticle.abstract???
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.
Amano,
Isolation of genes involved in intestinal remodeling during anuran metamorphosis.
1998, Pubmed,
Xenbase
Amano,
Isolation of genes involved in intestinal remodeling during anuran metamorphosis.
1998,
Pubmed
,
Xenbase
Bagamasbad,
A role for basic transcription element-binding protein 1 (BTEB1) in the autoinduction of thyroid hormone receptor beta.
2008,
Pubmed
,
Xenbase
Bilesimo,
Specific histone lysine 4 methylation patterns define TR-binding capacity and differentiate direct T3 responses.
2011,
Pubmed
,
Xenbase
Brown,
Amphibian metamorphosis.
2007,
Pubmed
,
Xenbase
Buchholz,
A dominant-negative thyroid hormone receptor blocks amphibian metamorphosis by retaining corepressors at target genes.
2003,
Pubmed
,
Xenbase
Buchholz,
Pairing morphology with gene expression in thyroid hormone-induced intestinal remodeling and identification of a core set of TH-induced genes across tadpole tissues.
2007,
Pubmed
,
Xenbase
Buchholz,
Transgenic analysis reveals that thyroid hormone receptor is sufficient to mediate the thyroid hormone signal in frog metamorphosis.
2004,
Pubmed
,
Xenbase
Buchholz,
Molecular and developmental analyses of thyroid hormone receptor function in Xenopus laevis, the African clawed frog.
2006,
Pubmed
,
Xenbase
Burke,
Co-repressors 2000.
2000,
Pubmed
Crosnier,
Organizing cell renewal in the intestine: stem cells, signals and combinatorial control.
2006,
Pubmed
Denver,
Thyroid hormone receptor subtype specificity for hormone-dependent neurogenesis in Xenopus laevis.
2009,
Pubmed
,
Xenbase
Flamant,
Congenital hypothyroid Pax8(-/-) mutant mice can be rescued by inactivating the TRalpha gene.
2002,
Pubmed
Friedrichsen,
Regulation of iodothyronine deiodinases in the Pax8-/- mouse model of congenital hypothyroidism.
2003,
Pubmed
Fujimoto,
Thyroid hormone activates protein arginine methyltransferase 1 expression by directly inducing c-Myc transcription during Xenopus intestinal stem cell development.
2012,
Pubmed
,
Xenbase
Harper,
The transcriptional repressor Blimp1/Prdm1 regulates postnatal reprogramming of intestinal enterocytes.
2011,
Pubmed
Hasebe,
Epithelial-connective tissue interactions induced by thyroid hormone receptor are essential for adult stem cell development in the Xenopus laevis intestine.
2011,
Pubmed
,
Xenbase
Havis,
Metamorphic T3-response genes have specific co-regulator requirements.
2003,
Pubmed
,
Xenbase
Heimeier,
Participation of Brahma-related gene 1 (BRG1)-associated factor 57 and BRG1-containing chromatin remodeling complexes in thyroid hormone-dependent gene activation during vertebrate development.
2008,
Pubmed
,
Xenbase
Heimeier,
The xenoestrogen bisphenol A inhibits postembryonic vertebrate development by antagonizing gene regulation by thyroid hormone.
2009,
Pubmed
,
Xenbase
Heimeier,
Studies on Xenopus laevis intestine reveal biological pathways underlying vertebrate gut adaptation from embryo to adult.
2010,
Pubmed
,
Xenbase
Hsia,
Chromatin disruption and histone acetylation in regulation of the human immunodeficiency virus type 1 long terminal repeat by thyroid hormone receptor.
2002,
Pubmed
,
Xenbase
Hu,
Transcriptional repression by nuclear hormone receptors.
2000,
Pubmed
Huang,
A role for cofactor-cofactor and cofactor-histone interactions in targeting p300, SWI/SNF and Mediator for transcription.
2003,
Pubmed
,
Xenbase
Ishizuya-Oka,
Origin of the adult intestinal stem cells induced by thyroid hormone in Xenopus laevis.
2009,
Pubmed
,
Xenbase
Ishizuya-Oka,
Evolutionary insights into postembryonic development of adult intestinal stem cells.
2011,
Pubmed
Ito,
The TRAP/SMCC/Mediator complex and thyroid hormone receptor function.
2001,
Pubmed
Jepsen,
Biological roles and mechanistic actions of co-repressor complexes.
2002,
Pubmed
Jones,
N-CoR-HDAC corepressor complexes: roles in transcriptional regulation by nuclear hormone receptors.
2003,
Pubmed
,
Xenbase
Kress,
The frizzled-related sFRP2 gene is a target of thyroid hormone receptor alpha1 and activates beta-catenin signaling in mouse intestine.
2009,
Pubmed
Lazar,
Thyroid hormone receptors: multiple forms, multiple possibilities.
1993,
Pubmed
MACDONALD,
CELL PROLIFERATION AND MIGRATION IN THE STOMACH, DUODENUM, AND RECTUM OF MAN: RADIOAUTOGRAPHIC STUDIES.
1964,
Pubmed
Mangelsdorf,
The nuclear receptor superfamily: the second decade.
1995,
Pubmed
Matsuda,
Novel functions of protein arginine methyltransferase 1 in thyroid hormone receptor-mediated transcription and in the regulation of metamorphic rate in Xenopus laevis.
2009,
Pubmed
,
Xenbase
Matsuda,
An essential and evolutionarily conserved role of protein arginine methyltransferase 1 for adult intestinal stem cells during postembryonic development.
2010,
Pubmed
,
Xenbase
Matsuura,
Liganded thyroid hormone receptor induces nucleosome removal and histone modifications to activate transcription during larval intestinal cell death and adult stem cell development.
2012,
Pubmed
,
Xenbase
Matsuura,
Histone H3K79 methyltransferase Dot1L is directly activated by thyroid hormone receptor during Xenopus metamorphosis.
2012,
Pubmed
,
Xenbase
Muncan,
Blimp1 regulates the transition of neonatal to adult intestinal epithelium.
2011,
Pubmed
Nakajima,
Dual mechanisms governing muscle cell death in tadpole tail during amphibian metamorphosis.
2003,
Pubmed
,
Xenbase
Paul,
Tissue- and gene-specific recruitment of steroid receptor coactivator-3 by thyroid hormone receptor during development.
2005,
Pubmed
,
Xenbase
Paul,
SRC-p300 coactivator complex is required for thyroid hormone-induced amphibian metamorphosis.
2007,
Pubmed
,
Xenbase
Paul,
Coactivator recruitment is essential for liganded thyroid hormone receptor to initiate amphibian metamorphosis.
2005,
Pubmed
,
Xenbase
Plateroti,
Involvement of T3Ralpha- and beta-receptor subtypes in mediation of T3 functions during postnatal murine intestinal development.
1999,
Pubmed
Plateroti,
Functional interference between thyroid hormone receptor alpha (TRalpha) and natural truncated TRDeltaalpha isoforms in the control of intestine development.
2001,
Pubmed
Plateroti,
Thyroid hormone receptor alpha1 directly controls transcription of the beta-catenin gene in intestinal epithelial cells.
2006,
Pubmed
Rachez,
Mediator complexes and transcription.
2001,
Pubmed
Rachez,
Mechanisms of gene regulation by vitamin D(3) receptor: a network of coactivator interactions.
2000,
Pubmed
Sachs,
Nuclear receptor corepressor recruitment by unliganded thyroid hormone receptor in gene repression during Xenopus laevis development.
2002,
Pubmed
,
Xenbase
Sancho,
Signaling pathways in intestinal development and cancer.
2004,
Pubmed
Sato,
A role of unliganded thyroid hormone receptor in postembryonic development in Xenopus laevis.
2007,
Pubmed
,
Xenbase
Schreiber,
Diverse developmental programs of Xenopus laevis metamorphosis are inhibited by a dominant negative thyroid hormone receptor.
2001,
Pubmed
,
Xenbase
Schreiber,
Remodeling of the intestine during metamorphosis of Xenopus laevis.
2005,
Pubmed
,
Xenbase
Schreiber,
Cell-cell interactions during remodeling of the intestine at metamorphosis in Xenopus laevis.
2009,
Pubmed
,
Xenbase
Shi,
The development of the adult intestinal stem cells: Insights from studies on thyroid hormone-dependent amphibian metamorphosis.
2011,
Pubmed
,
Xenbase
Shi,
The earliest changes in gene expression in tadpole intestine induced by thyroid hormone.
1993,
Pubmed
,
Xenbase
Shi,
Biphasic intestinal development in amphibians: embryogenesis and remodeling during metamorphosis.
1996,
Pubmed
,
Xenbase
Shi,
Dual functions of thyroid hormone receptors in vertebrate development: the roles of histone-modifying cofactor complexes.
2009,
Pubmed
,
Xenbase
Sun,
Spatio-temporal expression profile of stem cell-associated gene LGR5 in the intestine during thyroid hormone-dependent metamorphosis in Xenopus laevis.
2010,
Pubmed
,
Xenbase
Tata,
Gene expression during metamorphosis: an ideal model for post-embryonic development.
1993,
Pubmed
Tomita,
Recruitment of N-CoR/SMRT-TBLR1 corepressor complex by unliganded thyroid hormone receptor for gene repression during frog development.
2004,
Pubmed
,
Xenbase
Tsai,
Molecular mechanisms of action of steroid/thyroid receptor superfamily members.
1994,
Pubmed
Wong,
A role for nucleosome assembly in both silencing and activation of the Xenopus TR beta A gene by the thyroid hormone receptor.
1995,
Pubmed
,
Xenbase
Wong,
Determinants of chromatin disruption and transcriptional regulation instigated by the thyroid hormone receptor: hormone-regulated chromatin disruption is not sufficient for transcriptional activation.
1997,
Pubmed
,
Xenbase
Yen,
Physiological and molecular basis of thyroid hormone action.
2001,
Pubmed
Zhang,
The mechanism of action of thyroid hormones.
2000,
Pubmed
van der Flier,
Stem cells, self-renewal, and differentiation in the intestinal epithelium.
2009,
Pubmed
