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Cell Biosci
2013 Nov 13;31:43. doi: 10.1186/2045-3701-3-43.
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Differential regulation of two histidine ammonia-lyase genes during Xenopus development implicates distinct functions during thyroid hormone-induced formation of adult stem cells.
Luu N
,
Wen L
,
Fu L
,
Fujimoto K
,
Shi YB
,
Sun G
.
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BACKGROUND: Organ-specific, adult stem cells are essential for organ-homeostasis and tissue repair and regeneration. The formation of such stem cells during vertebrate development remains to be investigated. Frog metamorphosis offers an excellent opportunity to study the formation of adult stem cells as this process involves essentially the transformations of all larval tissues/organs into the adult form. Of particular interest is the remodeling of the intestine. Early studies in Xenopus laevis have shown that this process involves complete degeneration of the larval epithelium and de novo formation of adult stem cells through dedifferentiation of some larval epithelial cells. A major advantage of this metamorphosis model is its total dependence on thyroid hormone (T3). In an effort to identify genes that are important for stem cell development, we have previously carried out tissue-specific microarray analysis of intestinal gene expression during Xenopus laevis metamorphosis.
RESULTS: We report the detailed characterization of one of the genes thus identified, the histidine ammonia-lyase (HAL) gene, which encodes an enzyme known as histidase or histidinase. We show that there are two duplicated HAL genes, HAL1 and HAL2, in both Xenopus laevis and Xenopus tropicalis, a highly related but diploid species. Interestingly, only HAL2 is highly upregulated by T3 and appears to be specifically expressed in the adult intestinal progenitor/stem cells while HAL1 is not expressed in the intestine during metamorphosis. Furthermore, when analyzed in whole animals, HAL1 appears to be expressed only during embryogenesis but not metamorphosis while the opposite appears to be true for HAL2.
CONCLUSIONS: Our results suggest that the duplicated HAL genes have distinct functions with HAL2 likely involved in the formation and/or proliferation of the adult stem cells during metamorphosis.
Figure 1. The two Xenopus histidine ammonia lyase (HAL) genes encode proteins highly homologous to mammalian HAL. Sequence alignment was carried out among the human (h), mouse (m) and the three HALs from Xenopus laevis (xl) and two HALs Xenopus tropicalis (xt), a diploid species. Note that the proteins are highly homologous throughout the entire length. The HAL1 and HAL2 from Xenopus laevis and Xenopus tropicalis shared about 84% identity between each other, similar to their homologies to the mammalian HAL.
Figure 2. Phylogenetic tree of HALs from different species as shown in Figure1suggests that the two HAL genes were duplicated after the separation of mammals and amphibians but prior to the separation of
Xenopus laevis
and
Xenopus tropicalis
or that mammals lost the HAL1 gene during evolution.
Figure 3. Upregulation of HAL2 gene only in the epithelium during Xenopus laevis intestinal metamorphosis. The epithelium (Ep) and the rest of the intestine (non-Ep), which is made of mainly the connective tissue, were isolated from tadpoles at stage 56 (the onset of metamorphosis, also referred to as a premetamorphic stage), stage 61 (the climax of metamorphosis), and stage 66 (the end of metamorphosis) [27]. The total RNA from the Ep and non-Ep was used for qRT-PCR analysis of HAL2 gene expression. Note that HAL2 was exclusively expressed in the Ep at the climax of metamorphosis.
Figure 4. Upregulation of HAL2 during intestinal metamorphosis. Total RNA isolated from the intestine of animals from premetamorphic stage 54 to the end of metamorphosis (stage 66) was subjected to qRT-PCR analysis for HAL2 gene expression. Note that again HAL2 was found to have little or no expression before or after metamorphosis but was drastically upregulated during metamorphosis.
Figure 5. Dramatic upregulation of HAL2 by T3-treatment of premetamorphic tadpoles. Stage 54 premetamorphic tadpoles were treated with 10 nM T3 for 0-7 days and total intestinal RNA was isolated for expression analysis. Note that HAL2 expression was upregulated significantly after 1 day of treatment and the expression continued to increase dramatically during the treatment, peaking after 5 days.
Figure 6. In situ hybridization analysis suggests specific expression of HAL2 in the proliferating adult intestinal progenitor/stem cells. ISH on intestinal cross-sections at stages 54 (A), 61 (B), and 66 (C) was carried out with anti-sense probe for HAL2. An enlarged photo of the boxed areas (a, b, c) in the top panels are shown in the lower panels. Note that HAL2 staining was found to be in clusters of cells located in between the dying larval epithelial cells and connective tissue at the climax of metamorphosis, where the proliferating adult epithelial cells are located [8,19,36,48], consistent with the expression data in Figures 3 and 4. AE, adult epithelium; CT, connective tissue; Lu, lumen; LE, larval epithelium; M, muscle; Ty, typhlosole.
Figure 7. Distinct expression profiles of HAL1 and HAL2 during development. Total RNA isolated from whole animals from embryonic stage 30 to the end of metamorphosis (stage 66) was subjected to quantitative RT-PCR analysis for HAL1 and HAL2 gene expression. Note that HAL1 was expressed strongly in embryos and repressed after stage 45 when tadpole feeding begins while HAL2 was upregulated by stage 45 and its expression continued to rise till the end of metamorphosis.
AUERBACH,
Histidinemia. A deficiency in histidase resulting in the urinary excretion of histidine and of imidazolepyruvic acid.
1962, Pubmed
AUERBACH,
Histidinemia. A deficiency in histidase resulting in the urinary excretion of histidine and of imidazolepyruvic acid.
1962,
Pubmed
Amaya,
Frog genetics: Xenopus tropicalis jumps into the future.
1998,
Pubmed
,
Xenbase
Bilesimo,
Specific histone lysine 4 methylation patterns define TR-binding capacity and differentiate direct T3 responses.
2011,
Pubmed
,
Xenbase
Bulfield,
Histidinaemia in mouse and man.
1974,
Pubmed
Cheng,
Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. III. Entero-endocrine cells.
1974,
Pubmed
Das,
Identification of direct thyroid hormone response genes reveals the earliest gene regulation programs during frog metamorphosis.
2009,
Pubmed
,
Xenbase
Flamant,
Congenital hypothyroid Pax8(-/-) mutant mice can be rescued by inactivating the TRalpha gene.
2002,
Pubmed
Fu,
Genome-wide identification of Xenopus matrix metalloproteinases: conservation and unique duplications in amphibians.
2009,
Pubmed
,
Xenbase
Fujimoto,
One of the duplicated matrix metalloproteinase-9 genes is expressed in regressing tail during anuran metamorphosis.
2006,
Pubmed
,
Xenbase
Fujimoto,
Direct activation of Xenopus iodotyrosine deiodinase by thyroid hormone receptor in the remodeling intestine during amphibian metamorphosis.
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
Hasebe,
Spatial and temporal expression profiles suggest the involvement of gelatinase A and membrane type 1 matrix metalloproteinase in amphibian metamorphosis.
2006,
Pubmed
,
Xenbase
Hasebe,
Thyroid hormone-induced cell-cell interactions are required for the development of adult intestinal stem cells.
2013,
Pubmed
,
Xenbase
Hasebe,
Evidence for a cooperative role of gelatinase A and membrane type-1 matrix metalloproteinase during Xenopus laevis development.
2007,
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
Ishizuya-Oka,
Anteroposterior gradient of epithelial transformation during amphibian intestinal remodeling: immunohistochemical detection of intestinal fatty acid-binding protein.
1997,
Pubmed
,
Xenbase
Ishizuya-Oka,
Origin of the adult intestinal stem cells induced by thyroid hormone in Xenopus laevis.
2009,
Pubmed
,
Xenbase
Ishizuya-Oka,
Ultrastructural changes in the intestinal connective tissue of Xenopus laevis during metamorphosis.
1987,
Pubmed
,
Xenbase
Ishizuya-Oka,
Inductive action of epithelium on differentiation of intestinal connective tissue of Xenopus laevis tadpoles during metamorphosis in vitro.
1994,
Pubmed
,
Xenbase
Ishizuya-Oka,
Evolutionary insights into postembryonic development of adult intestinal stem cells.
2011,
Pubmed
Ishizuya-Oka,
Development of the connective tissue in the digestive tract of the larval and metamorphosing Xenopus laevis.
1987,
Pubmed
,
Xenbase
Ishizuya-Oka,
Apoptosis and cell proliferation in the Xenopus small intestine during metamorphosis.
1996,
Pubmed
,
Xenbase
Ishizuya-Oka,
Establishment of intestinal stem cell niche during amphibian metamorphosis.
2013,
Pubmed
,
Xenbase
Ishizuya-Oka,
Connective tissue is involved in adult epithelial development of the small intestine during anuran metamorphosis in vitro.
1992,
Pubmed
Kacser,
Maternal histidine metabolism and its effect on foetal development in the mouse.
1977,
Pubmed
Kawai,
Molecular characterization of histidinemia: identification of four missense mutations in the histidase gene.
2005,
Pubmed
Kress,
The frizzled-related sFRP2 gene is a target of thyroid hormone receptor alpha1 and activates beta-catenin signaling in mouse intestine.
2009,
Pubmed
Kuroda,
Relationship between skin histidase activity and blood histidine response to histidine intake in patients with histidinemia.
1980,
Pubmed
MACDONALD,
CELL PROLIFERATION AND MIGRATION IN THE STOMACH, DUODENUM, AND RECTUM OF MAN: RADIOAUTOGRAPHIC STUDIES.
1964,
Pubmed
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
Patterton,
Thyroid hormone-dependent differential regulation of multiple arginase genes during amphibian metamorphosis.
1994,
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
Sancho,
Signaling pathways in intestinal development and cancer.
2004,
Pubmed
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,
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
Sterling,
Cytological and morphological analyses reveal distinct features of intestinal development during Xenopus tropicalis metamorphosis.
2012,
Pubmed
,
Xenbase
Suchi,
Molecular cloning and structural characterization of the human histidase gene (HAL).
1995,
Pubmed
Suchi,
Molecular cloning of a cDNA encoding human histidase.
1993,
Pubmed
Sun,
Thyroid hormone regulation of adult intestinal stem cell development: mechanisms and evolutionary conservations.
2012,
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,
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
Taylor,
Histidase and histidinemia. Clinical and molecular considerations.
1991,
Pubmed
Wang,
Dependence of mouse embryonic stem cells on threonine catabolism.
2009,
Pubmed
,
Xenbase
Wang,
Developmental regulation and function of thyroid hormone receptors and 9-cis retinoic acid receptors during Xenopus tropicalis metamorphosis.
2008,
Pubmed
,
Xenbase
van der Flier,
Stem cells, self-renewal, and differentiation in the intestinal epithelium.
2009,
Pubmed
