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.
Genome Biol
2010 Jan 01;115:R55. doi: 10.1186/gb-2010-11-5-r55.
Show Gene links
Show Anatomy links
Studies on Xenopus laevis intestine reveal biological pathways underlying vertebrate gut adaptation from embryo to adult.
Heimeier RA
,
Das B
,
Buchholz DR
,
Fiorentino M
.
???displayArticle.abstract???
To adapt to its changing dietary environment, the digestive tract is extensively remodeled from the embryo to the adult during vertebrate development. Xenopus laevis metamorphosis is an excellent model system for studying mammalian gastrointestinal development and is used to determine the genes and signaling programs essential for intestinal development and maturation. The metamorphosing intestine can be divided into four distinct developmental time points and these were analyzed with X. laevis microarrays. Due to the high level of conservation in developmental signaling programs and homology to mammalian genes, annotations and bioinformatics analysis were based on human orthologs. Clustering of the expression patterns revealed co-expressed genes involved in essential cell processes such as apoptosis and proliferation. The two largest clusters of genes have expression peaks and troughs at the climax of metamorphosis, respectively. Novel conserved gene ontology categories regulated during this period include transcriptional activity, signal transduction, and metabolic processes. Additionally, we identified larval/embryo- and adult-specific genes. Detailed analysis revealed 17 larval specific genes that may represent molecular markers for human colonic cancers, while many adult specific genes are associated with dietary enzymes. This global developmental expression study provides the first detailed molecular description of intestinal remodeling and maturation during postembryonic development, which should help improve our understanding of intestinal organogenesis and human diseases. This study significantly contributes towards our understanding of the dynamics of molecular regulation during development and tissue renewal, which is important for future basic and clinical research and for medicinal applications.
Figure 9. In situ hybridization of the four adult-specific genes with intestinal cross-sections at stages 53 and 66. Scale bar = 100 μm. AE: adult epithelium; Ct: connective tissue; Ep: epithelium; L: lumen; M: muscle; Ty: typhlosole.
Figure 2. Expression changes of TRβ, THb/ZIP, ST3, XHH, GelA and IFABP, which are established intestinal remodeling markers, during natural development. The results are expressed relative to the control rpl8.
Figure 3. Genes significantly up- and down-regulated in the intestine during natural metamorphosis at specific stages when compared to stage 53. Venn diagrams showing the number of genes significantly (a) up-regulated and (b) down-regulated in the intestine during natural metamorphosis when the indicated stages were compared to stage 53 by microarray. (c) Temporal changes in gene expression during natural development visualized by heatmap. Normalized mean-centered expression levels for each gene are shown with black representing mean expression levels of four stages for a given gene, and green and red indicating lower or higher than the average as shown in the color legend.
Figure 4. Confirmation of gene regulation patterns identified by microarray with RT-qPCR. (a) Microarray. (b) RT-qPCR. GenBank accession numbers are shown above the graphs. The vertical axis in (a) shows the normalized log intensity of the expression and in (b) shows the expression of the genes with stage 53 arbitrarily set to 1.
Figure 5. Regulated genes can be grouped into six clusters based on developmental regulation patterns. The number of genes in each cluster is indicated in the schematic diagram. (a, b) Clusters 1 and 2 represent genes that are predominantly regulated at metamorphic climax, with the former following the endogenous T3 concentration. (c, d) Clusters 3 and 4 include genes with higher levels of expression in tadpoles and frogs (larval- and adult-enriched genes), respectively. (e, f) Clusters 5 and 6 are genes up- or down-regulated mainly at stage 58. All clusters were evaluated by GO analysis and two or more examples of the significantly regulated GO categories that had >60 genes (clusters 1 and 2) and >5 genes (clusters 3 to 6) regulated during metamorphosis are listed. A complete list of GO categories associated with each cluster is listed in Table S6 in Additional file 1. PCA: principal component analysis.
Figure 6. Temporal regulation of a significantly regulated biological pathway, the TGF-β pathway, during intestinal remodeling. Genes that are up- or down-regulated at stages 58, 61 and 66 relative to stage 53 are shown in red and green, respectively.
Figure 7. Temporal regulation of the electron transport pathway during intestinal remodeling. Genes that are up- or down-regulated at stages 58, 61 and 66 relative to stage 53 are shown in red and green, respectively.
Figure 8. The expression of larval- and adult-specific genes during natural metamorphosis. Larval- and adult-specific genes analyzed by RT-qPCR, confirming the larval- and adult-specific designation based on microarray analysis.
Figure 10. Gene expression during mouse development. RT-qPCR analysis was carried out for the indicated genes on mouse intestinal RNA at indicated stages. Note that the expression patterns of mouse EB13, FCNA, MMP11, MMP14, PPP1RA1 and SLC7A2 were similar to those of their homologs in Xenopus during metamorphosis as observed by microarray, that is, there were higher levels of expression shortly after birth in the mouse when T3 levels are high, just like at metamorphic climax. The expression of NPL and RENBP represent profiles of genes that differ from those in Xenopus. All RT-qPCR results are expressed relative to the control RPS13, with the expression of the genes at E17 arbitrarily set to 1.
,
,
Pubmed
Allen,
Transformation by oncogenic Ras expands the early genomic response to transforming growth factor beta in intestinal epithelial cells.
2008,
Pubmed
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,
Molecular and developmental analyses of thyroid hormone receptor function in Xenopus laevis, the African clawed frog.
2006,
Pubmed
,
Xenbase
Bulus,
Ras-mediated suppression of TGFbetaRII expression in intestinal epithelial cells involves Raf-independent signaling.
2000,
Pubmed
Cheng,
Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. III. Entero-endocrine cells.
1974,
Pubmed
Crosnier,
Organizing cell renewal in the intestine: stem cells, signals and combinatorial control.
2006,
Pubmed
Dahlquist,
GenMAPP, a new tool for viewing and analyzing microarray data on biological pathways.
2002,
Pubmed
Das,
Gene expression changes at metamorphosis induced by thyroid hormone in Xenopus laevis tadpoles.
2006,
Pubmed
,
Xenbase
Dauça,
Development of the vertebrate small intestine and mechanisms of cell differentiation.
1990,
Pubmed
Doniger,
MAPPFinder: using Gene Ontology and GenMAPP to create a global gene-expression profile from microarray data.
2003,
Pubmed
Fu,
A causative role of stromelysin-3 in extracellular matrix remodeling and epithelial apoptosis during intestinal metamorphosis in Xenopus laevis.
2005,
Pubmed
,
Xenbase
Ghosh,
Paneth cell trypsin is the processing enzyme for human defensin-5.
2002,
Pubmed
Hasebe,
Spatial and temporal expression profiles suggest the involvement of gelatinase A and membrane type 1 matrix metalloproteinase in amphibian metamorphosis.
2006,
Pubmed
,
Xenbase
Heimeier,
The xenoestrogen bisphenol A inhibits postembryonic vertebrate development by antagonizing gene regulation by thyroid hormone.
2009,
Pubmed
,
Xenbase
Huang,
C2GnT-M is downregulated in colorectal cancer and its re-expression causes growth inhibition of colon cancer cells.
2006,
Pubmed
Koshikawa,
Expression of trypsin by epithelial cells of various tissues, leukocytes, and neurons in human and mouse.
1998,
Pubmed
Liu,
DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis.
1997,
Pubmed
Liu,
Co-expression of cytokeratin 8 and breast cancer resistant protein indicates a multifactorial drug-resistant phenotype in human breast cancer cell line.
2008,
Pubmed
Muraoka,
Increased malignancy of Neu-induced mammary tumors overexpressing active transforming growth factor beta1.
2003,
Pubmed
Neurath,
Evolution of proteolytic enzymes.
1984,
Pubmed
Pearce,
Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium.
2009,
Pubmed
Saeed,
TM4: a free, open-source system for microarray data management and analysis.
2003,
Pubmed
Sancho,
Signaling pathways in intestinal development and cancer.
2004,
Pubmed
Schreiber,
Remodeling of the intestine during metamorphosis of Xenopus laevis.
2005,
Pubmed
,
Xenbase
Shaheduzzaman,
Silencing of Lactotransferrin expression by methylation in prostate cancer progression.
2007,
Pubmed
Sharov,
A web-based tool for principal component and significance analysis of microarray data.
2005,
Pubmed
Shi,
Biphasic intestinal development in amphibians: embryogenesis and remodeling during metamorphosis.
1996,
Pubmed
,
Xenbase
Shi,
Cloning and characterization of the ribosomal protein L8 gene from Xenopus laevis.
1994,
Pubmed
,
Xenbase
Simon,
Intestinal epithelial cell differentiation: new insights from mice, flies and nematodes.
1995,
Pubmed
Stuckenholz,
FACS-assisted microarray profiling implicates novel genes and pathways in zebrafish gastrointestinal tract development.
2009,
Pubmed
Suman,
Novel mutations of CYP3A4 in fine needle aspiration cytology samples of breast cancer patients and its clinical correlations.
2009,
Pubmed
Tata,
Gene expression during metamorphosis: an ideal model for post-embryonic development.
1993,
Pubmed
van der Flier,
Stem cells, self-renewal, and differentiation in the intestinal epithelium.
2009,
Pubmed
Vasiliou,
Human ATP-binding cassette (ABC) transporter family.
2009,
Pubmed
Zeeberg,
GoMiner: a resource for biological interpretation of genomic and proteomic data.
2003,
Pubmed
