Fu L , Yin J .

ZIA HD001901-23 Intramural NIH HHS, ZIA HD008858-10 Intramural NIH HHS, ZIA HD008858-11 Intramural NIH HHS

	Fig. 1. Xenopus intestinal metamorphosis serves as a model for studying adult organ-specific stem cell development in vertebrates. In premetamorphic tadpoles (e.g., at stage 51), the intestine has only a single fold, the typhlosole, where connective tissue is abundant, and is structurally similar to the mammalian embryonic intestine. At the metamorphic climax around stage 61, the vast majority of the larval epithelial cells undergo apoptosis (the open circles). A small fraction of the larval epithelial cells undergo dedifferentiation into cells that rapidly proliferate (EdU positive) and express the adult stem cell marker Lgr5 (black dots in the stage 61 diagram). By stage 66 (the end of metamorphosis), these cells differentiate to form a multiply folded epithelium surrounded by elaborate connective tissue and thick muscle layers. See (Okada et al., 2015) for EdU labeling and Lgr5 in situ hybridization.
	Fig. 2. Regulation of T3-inducible genes by TR during Xenopus development. In premetamorphic tadpoles, there is little T3 and TR is unliganded. The unliganded TR/RXR heterodimer binds to TREs in the target genes and recruits corepressor complexes such as the N-CoR-HDAC3 complex, resulting in the reduction in the levels of activation histone marks and increase of repression marks, and consequently gene repression. During metamorphosis, high levels of T3 leads to T3-binding to TR. Liganded TR/RXR recruits coactivator complexes such as SRC complexes as shown to disrupt chromatin and modify histones, leading to increased levels of activation histone marks and gene activation. N-CoR: nuclear corepressor, HDAC: histone deacetylase, SRC3: steroid receptor coactivator 3 (a histone acetyltransferase), p300: a histone acetyltransferase, PRMT1: protein arginine methyltransferase 1.
	Fig. 3. A positive feedback mechanism to enhance T3 activation of gene transcription through histone methylation. T3 induces the expression of Dot1L directly at the transcription level (Matsuura et al., 2012a) and PRMT1 indirectly via transcriptional activation of cMyc by TR in the developing stem cells (Fujimoto et al., 2012, Okada et al., 2017). Dot1L and PRMT1 in turn function as TR coactivators to increase local histone methylations to enhance transcription (Fujimoto et al., 2012, Wen et al., 2017a). It is worth pointing out that there has been no direct evidence for the recruitment of Dot1L to TREs, although PRMT1 has been shown to be recruited by TR to TREs in the presence of T3 during metamorphosis (Matsuda et al., 2009).

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
Bochukova, A mutation in the thyroid hormone receptor alpha gene. 2012, Pubmed
Brown, Amphibian metamorphosis. 2007, 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, Dual function model revised by thyroid hormone receptor alpha knockout frogs. 2018, Pubmed , Xenbase
Buchholz, A dominant-negative thyroid hormone receptor blocks amphibian metamorphosis by retaining corepressors at target genes. 2003, Pubmed , Xenbase
Buchholz, Molecular and developmental analyses of thyroid hormone receptor function in Xenopus laevis, the African clawed frog. 2006, Pubmed , Xenbase
Buchholz, Transgenic analysis reveals that thyroid hormone receptor is sufficient to mediate the thyroid hormone signal in frog metamorphosis. 2004, Pubmed , Xenbase
Chen, Regulation of transcription by a protein methyltransferase. 1999, Pubmed
Choi, Growth, Development, and Intestinal Remodeling Occurs in the Absence of Thyroid Hormone Receptor α in Tadpoles of Xenopus tropicalis. 2017, Pubmed , Xenbase
Choi, Unliganded thyroid hormone receptor α regulates developmental timing via gene repression in Xenopus tropicalis. 2015, Pubmed , Xenbase
Das, Identification of direct thyroid hormone response genes reveals the earliest gene regulation programs during frog metamorphosis. 2009, Pubmed , Xenbase
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
Fu, Genome-wide identification of thyroid hormone receptor targets in the remodeling intestine during Xenopus tropicalis metamorphosis. 2017, Pubmed , Xenbase
Fu, Roles of Matrix Metalloproteinases and ECM Remodeling during Thyroid Hormone-Dependent Intestinal Metamorphosis in Xenopus laevis. 2007, Pubmed , Xenbase
Fujimoto, Thyroid hormone activates protein arginine methyltransferase 1 expression by directly inducing c-Myc transcription during Xenopus intestinal stem cell development. 2012, Pubmed , Xenbase
Grimaldi, Mechanisms of thyroid hormone receptor action during development: lessons from amphibian studies. 2013, Pubmed , Xenbase
Harper, The transcriptional repressor Blimp1/Prdm1 regulates postnatal reprogramming of intestinal enterocytes. 2011, Pubmed
Hasebe, Thyroid Hormone-Induced Activation of Notch Signaling is Required for Adult Intestinal Stem Cell Development During Xenopus Laevis Metamorphosis. 2017, Pubmed , Xenbase
Hasebe, Thyroid hormone-up-regulated hedgehog interacting protein is involved in larval-to-adult intestinal remodeling by regulating sonic hedgehog signaling pathway in Xenopus laevis. 2008, Pubmed , Xenbase
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
Hasebe, Thyroid hormone activates Wnt/β-catenin signaling involved in adult epithelial development during intestinal remodeling in Xenopus laevis. 2016, Pubmed , Xenbase
Hasebe, Thyroid hormone-induced sonic hedgehog signal up-regulates its own pathway in a paracrine manner in the Xenopus laevis intestine during metamorphosis. 2012, Pubmed , Xenbase
Havis, Metamorphic T3-response genes have specific co-regulator requirements. 2003, 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
Ishizuya-Oka, Programmed cell death and heterolysis of larval epithelial cells by macrophage-like cells in the anuran small intestine in vivo and in vitro. 1992, Pubmed , Xenbase
Ishizuya-Oka, Apoptosis in amphibian organs during metamorphosis. 2010, Pubmed
Ishizuya-Oka, Connective tissue is involved in adult epithelial development of the small intestine during anuran metamorphosis in vitro. 1992, Pubmed
Ishizuya-Oka, Establishment of intestinal stem cell niche during amphibian metamorphosis. 2013, Pubmed , Xenbase
Ishizuya-Oka, Thyroid hormone-regulated Wnt5a/Ror2 signaling is essential for dedifferentiation of larval epithelial cells into adult stem cells in the Xenopus laevis intestine. 2014, Pubmed , Xenbase
Ishizuya-Oka, Shh/BMP-4 signaling pathway is essential for intestinal epithelial development during Xenopus larval-to-adult remodeling. 2006, Pubmed , Xenbase
Ishizuya-Oka, Origin of the adult intestinal stem cells induced by thyroid hormone in Xenopus laevis. 2009, Pubmed , Xenbase
Ishizuya-Oka, Induction of metamorphosis by thyroid hormone in anuran small intestine cultured organotypically in vitro. 1991, Pubmed , Xenbase
Ishizuya-Oka, Thyroid hormone-induced expression of sonic hedgehog correlates with adult epithelial development during remodeling of the Xenopus stomach and intestine. 2001, 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
Lei, Generation of gene disruptions by transcription activator-like effector nucleases (TALENs) in Xenopus tropicalis embryos. 2013, Pubmed , Xenbase
Lei, Efficient targeted gene disruption in Xenopus embryos using engineered transcription activator-like effector nucleases (TALENs). 2012, Pubmed , Xenbase
Luu, Differential regulation of two histidine ammonia-lyase genes during Xenopus development implicates distinct functions during thyroid hormone-induced formation of adult stem cells. 2013, Pubmed , Xenbase
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
Mathew, Tissue-dependent induction of apoptosis by matrix metalloproteinase stromelysin-3 during amphibian metamorphosis. 2010, Pubmed , Xenbase
Mathew, Differential regulation of cell type-specific apoptosis by stromelysin-3: a potential mechanism via the cleavage of the laminin receptor during tail resorption 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
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
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
Miller, Tissue-specific upregulation of MDS/EVI gene transcripts in the intestine by thyroid hormone during Xenopus metamorphosis. 2013, Pubmed , Xenbase
Moran, Resistance to thyroid hormone due to defective thyroid receptor alpha. 2015, Pubmed
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
Nakajima, Thyroid Hormone Receptor α- and β-Knockout Xenopus tropicalis Tadpoles Reveal Subtype-Specific Roles During Development. 2018, Pubmed , Xenbase
Nguyen, The diverse functions of Dot1 and H3K79 methylation. 2011, Pubmed
Okada, A balance of Mad and Myc expression dictates larval cell apoptosis and adult stem cell development during Xenopus intestinal metamorphosis. 2017, Pubmed , Xenbase
Okada, Molecular and cytological analyses reveal distinct transformations of intestinal epithelial cells during Xenopus metamorphosis. 2015, Pubmed , Xenbase
Okada, EVI and MDS/EVI are required for adult intestinal stem cell formation during postembryonic vertebrate development. 2018, 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, Thyroid hormone receptor alpha1 directly controls transcription of the beta-catenin gene in intestinal epithelial cells. 2006, Pubmed
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
Sachs, Targeted chromatin binding and histone acetylation in vivo by thyroid hormone receptor during amphibian development. 2000, Pubmed , Xenbase
Sachs, Unliganded thyroid hormone receptor function: amphibian metamorphosis got TALENs. 2015, Pubmed , Xenbase
Sachs, Dual functions of thyroid hormone receptors during Xenopus development. 2000, Pubmed , Xenbase
Sachs, Nuclear receptor corepressor recruitment by unliganded thyroid hormone receptor in gene repression during Xenopus laevis development. 2002, Pubmed , Xenbase
Sakane, Functional analysis of thyroid hormone receptor beta in Xenopus tropicalis founders using CRISPR-Cas. 2018, Pubmed , Xenbase
Schreiber, Diverse developmental programs of Xenopus laevis metamorphosis are inhibited by a dominant negative thyroid hormone receptor. 2001, Pubmed , Xenbase
Schreiber, Cell-cell interactions during remodeling of the intestine at metamorphosis in Xenopus laevis. 2009, Pubmed , Xenbase
Schreiber, Remodeling of the intestine during metamorphosis of Xenopus laevis. 2005, Pubmed , Xenbase
Shi, Dual functions of thyroid hormone receptors in vertebrate development: the roles of histone-modifying cofactor complexes. 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, Thyroid hormone receptor actions on transcription in amphibia: The roles of histone modification and chromatin disruption. 2012, Pubmed
Shi, Molecular biology of amphibian metamorphosis A new approach to an old problem. 1994, Pubmed
Sterling, Cytological and morphological analyses reveal distinct features of intestinal development during Xenopus tropicalis metamorphosis. 2012, Pubmed , Xenbase
Stolow, Xenopus sonic hedgehog as a potential morphogen during embryogenesis and thyroid hormone-dependent metamorphosis. 1995, Pubmed , Xenbase
Su, Cyclosporin A but not FK506 inhibits thyroid hormone-induced apoptosis in tadpole intestinal epithelium. 1997, Pubmed , Xenbase
Su, Thyroid hormone induces apoptosis in primary cell cultures of tadpole intestine: cell type specificity and effects of extracellular matrix. 1997, Pubmed , Xenbase
Sun, Expression profiling of intestinal tissues implicates tissue-specific genes and pathways essential for thyroid hormone-induced adult stem cell development. 2013, Pubmed , Xenbase
Sun, Thyroid hormone regulation of adult intestinal stem cell development: mechanisms and evolutionary conservations. 2012, Pubmed , Xenbase
Sun, Thyroid hormone regulation of adult intestinal stem cells: Implications on intestinal development and homeostasis. 2016, Pubmed , Xenbase
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
van der Flier, Stem cells, self-renewal, and differentiation in the intestinal epithelium. 2009, Pubmed
van Mullem, Clinical phenotype and mutant TRα1. 2012, Pubmed
Wen, Histone methyltransferase Dot1L is a coactivator for thyroid hormone receptor during Xenopus development. 2017, Pubmed , Xenbase
Wen, Thyroid Hormone Receptor α Controls Developmental Timing and Regulates the Rate and Coordination of Tissue-Specific Metamorphosis in Xenopus tropicalis. 2017, Pubmed , Xenbase
Wen, Regulation of growth rate and developmental timing by Xenopus thyroid hormone receptor α. 2016, Pubmed , Xenbase
Wen, Unliganded thyroid hormone receptor α controls developmental timing in Xenopus tropicalis. 2015, Pubmed , Xenbase
Wen, Histone methyltransferase Dot1L plays a role in postembryonic development in Xenopus tropicalis. 2015, Pubmed , Xenbase
Wen, A requirement for hedgehog signaling in thyroid hormone-induced postembryonic intestinal remodeling. 2015, Pubmed , Xenbase
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, Distinct requirements for chromatin assembly in transcriptional repression by thyroid hormone receptor and histone deacetylase. 1998, Pubmed , Xenbase
Wong, Coordinated regulation of and transcriptional activation by Xenopus thyroid hormone and retinoid X receptors. 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, Unliganded TRs regulate growth and developmental timing during early embryogenesis: evidence for a dual function mechanism of TR action. 2015, Pubmed , Xenbase
Yen, Physiological and molecular basis of thyroid hormone action. 2001, Pubmed
Young, Efficient targeted gene disruption in the soma and germ line of the frog Xenopus tropicalis using engineered zinc-finger nucleases. 2011, Pubmed , Xenbase