Shibata Y , Tanizaki Y , Zhang H , Lee H , Dasso M , Shi YB .

Intramural research Eunice Kennedy Shriver National Institute of Child Health and Human Development, postdoctoral fellowship Japan Society for the Promotion of Science

             intestinal epithelial cell differentiation

	Figure 1 TR double knockout inhibits natural intestine shortening at the climax of metamorphosis. The total body length (A) and the intestine length (B) were measured for wild-type and TRDKO tadpoles at the indicated stages. The relative intestine length (C) was obtained by normalizing the intestine length against the total body length at the indicated stages. At least 4 tadpoles were analyzed for each sample. Asterisks (***) indicate a significant difference vs. stage 58 for the 2 genotypes (p < 0.001, Bonfferoni comparison test). ns: No significant difference.
	Figure 2 TRDKO tadpoles have abnormal intestinal morphology with apparent adult type epithelial folding by stage 58. (A) Abnormal intestinal morphology in TRDKO tadpoles. Cross-sections of the intestine isolated from tadpoles at the indicated stages were stained with MGPY (methyl green-pyronin Y). (a,c,e): Wild-type TRα (+/+)TRβ (+/+); and (b,d,f): TR double knockout (TRDKO) TRα (−/−)TRβ (−/−). Dashed boxes in e and f for stage 61 are shown in higher magnification in e’ and f’, respectively. White arrowheads point to the clusters of proliferating adult epithelial stem cells adjacent to/underlying the degenerating larval epithelium (vacuole-like, poorly stained) at the climax of metamorphosis (stage 61) in wild-type animals. Note that the knockout tadpoles lacked such clusters at stage 61 and the epithelium appeared to be uniform without any obvious degeneration throughout the stages, but with numerous folds by stage 58. T: typhlosole. Bars: 100 μm. (B) TRDKO intestine does not have T3-induced tissue remodeling. Cross-sections of the intestine isolated from stage 54 tadpoles with or without 5 days T3 treatment were stained with MGPY. (a,b): TRα (+/+)TRβ (+/+); and (c,d): TRα (−/−)TRβ (−/−). Note that after T3 treatment, the wild-type intestine resembled that at stage 61 (climax of intestinal remodeling), while no T3-induced changes were present in the TRDKO tadpole intestine. T: typhlosole. Bars: 100 μm.
	Figure 3 TRDKO tadpoles have little or no cell proliferation or apoptosis at the climax of metamorphosis. (A,B) TRDKO inhibits epithelial cell proliferation. (A) Cross-sections of the intestine isolated from wild type (a,b) and TRDKO (c,d) tadpoles at stage 61 preinjected with EdU to label proliferating cells were stained for the presence of EdU. The dotted lines depict the epithelium–mesenchyme boundary, drawn based on morphological differences between epithelial cells and mesenchyme cells in the pictures of the stained tissues. EdU, red-color (a,c) and Hoechst, blue-color (b,d). T: typhlosole. Bars: 100 μm. (B) Quantification of the EdU positive area from at least 3 tadpoles for each genotype. The statistical significance of differences was determined by Student’s t-test. ***, p < 0.0001. (C,D) TRDKO inhibits larval epithelial cell death. (C) Cross-sections of the intestine isolated from wild type (a,b) and TRDKO (c,d) tadpoles at stage 61 were subjected to TUNEL labeling for apoptotic cells and Hoechst 33342 staining for DNA. The dotted lines depict the epithelium–mesenchyme boundary, drawn based on morphological differences between epithelial cells and mesenchyme cells in the pictures of the stained tissues. TUNEL: green, and Hoechst: blue. T: typhlosole. Bars: 100 μm. (D) Quantification of TUNEL-positive area from at least 3 tadpoles for each genotype. The statistical significance of differences was determined by Student’s t-test. **, p < 0.001.
	Figure 4 TRDKO accelerates intestinal muscle development during metamorphosis. Cross-sections of the intestine isolated from wild type (a–d) and TRDKO (e–g) tadpoles at stage 54 (a and e), stage 58 (b and f), stage 61 (c and g), and stage 66 (d) were stained with α-smooth actin (α-SMA, red) to label muscle cells in the nonepithelial cell layer. Dashed boxes in the left panels are shown at higher magnification in the right panels for each genotype, respectively. The dotted lines depict the muscularis–serosa boundary, drawn based on morphological differences between muscle cells and serosa cells in the pictures of the stained tissues. α-SMA, red-color and Hoechst, blue-color for DNA staining. T: typhlosole and L: lumen. Arrowheads: serosa, and asterisks: Muscularis. Shown are representative from at least 3 tadpoles analyzed for each genotype at different stages. Note that the precocious muscle development, indicated by *, in TRDKO tadpoles by stage 58 compared to the wild-type tadpoles. Bars: 100 μm.
	Figure 5 T3 response genes fail to be upregulated in the intestine of TRDKO tadpoles during metamorphosis. Total RNA was isolated from the intestine of wild-type and TRDKO tadpoles at stage 54, 58, and 61, and used for real-time RT-PCR analysis of the expression of known T3 direct-target genes: TR®, klf9, and TH/bzip; genes related to extracellular matrix remodeling: mmp2, mmp9, mmp11, mmp13, and mmp14; apoptosis-related genes: caspase 3, caspase 9, and bax; adult stem cell marker genes: sonic hedgehog (xhh) and olfm4, and cell dedifferentiation-related genes: ror2 and wnt5a. The mRNA levels were normalized against that of rpl8. The groups included 5 wild-type and 8 TRKDO animals. Note that the expression of all genes that are regulated during intestinal remodeling in the wild-type animals was essentially unchanged in the TRDKO animals. Asterisks (* and ***) indicate a significant difference determined by Bonfferoni comparison test (p < 0.05 and p < 0.001). nd: Not detected.
	Figure 6 TR double knockout inhibits the upregulation of genes in the GO categories involved in major intestinal remodeling processes: stem cell, cell proliferation, and apoptosis, at stage 61 during metamorphosis, but derepresses genes in ECM remodeling at premetamorphic stage 54. (A) Venn diagram analysis of genes regulated during intestinal metamorphosis in wild-type and TRDKO tadpoles shows that the vast majority of the regulated genes are different between the wild-type and TRDKO animals. RNA-seq was carried out on intestinal RNA from wild-type and TRDKO tadpoles at premetamorphic stage 54 and climax stage 61. Genes up- or down-regulated at stage 61 compared to stage 54 (2 folds or more) were identified for each genotype and compared. Note that there were much fewer genes regulated in the TRDKO animals. (B) Venn diagrams and heat maps reveal that TRDKO tadpoles have drastically reduced number of regulated genes at stage 61 in the three GO categories critical for intestinal remodeling: stem cell, cell proliferation, and apoptosis. Top: All genes in each of the three GO categories were identified from the up- and down-regulated genes in each genotype as found in (A) and compared by Venn diagram analysis between the two genotypes. Note that again most of the genes did not overlap between the two genotypes. Bottom: Heat maps of the expression of all genes in each GO category at the two stages for the two genotypes. Note the coordinated upregulation of most of the genes in each GO category at stage 61 compared to stage 54 in the wild-type intestine but not in the TRDKO intestine. (C) GO analysis reveals that GO categories related to ECM remodeling (shown in red) are significantly enriched among genes expressed at higher levels in the stage 54 intestine of TRDKO tadpoles compared to the wild-type ones. The RNA-seq data from (A) were used to identify genes that were expressed at higher levels (2-fold or more) in the stage 54 intestine of TRDKO tadpoles compared to the wild type ones. The 3187 genes thus identified were subjected to GO analysis, and the top 10 enriched GO terms are shown. (D) Heat maps of the expression of MMP genes at the two developmental stages (54, or premetamorphosis, and 61, or metamorphic climax) for the two genotypes. Note that essentially all MMPs genes were upregulated at stage 61 compared to stage 54 in wild-type but not TRDKO intestine and many of the MMPs genes were expressed at higher levels (2-fold or more) in the TRDKO intestine compared the wild-type intestine at stage 54 (genes in red), suggesting that they were derepressed upon TR knockout.
	Figure 7 TR-dependent regulation of genes in the Wnt signaling pathway, a representative pathway likely involved in the development of adult intestinal stem cells, as revealed by RNA-seq analysis. Up- and down-regulated genes in the intestine at stage 61 compared to stage 54 in each genotype are shown in red and green, respectively (color keys, log2 fold change). Note that many more genes were upregulated (red) at stage 61 in the wild-type tadpoles (Top) compared to TRDKO animals, and the reverse was true for down-regulated genes (green). Two blue arrows point to dvl genes, which are known as the hub of Wnt signaling critical for relaying Wnt signal from receptors to downstream effectors [62] that were upregulated at stage 61 in the wild-type animals (dvl2 and dvl3), but downregulated at stage 61 in the TRDKO animals (dvl1).
	Supplemental Figure 1. [A-D] TR double knockout tadpoles with a homozygous 29 base-out-frame deletion (14 base in exon and 15 base in intron) of TRb gene locus shows similar intestinal remodeling defects as TR double knockout tadpoles with a homozygous 19 base-out-frame mutation of TRb gene locus. (A) Schematic diagram depicting the sequence of the TALEN-target region in wild type and TRa mutants (16 base-deletion and 9 base- insertion) animals. All TR double knockout animals have this TRa mutation. The protein coding exons are shown as numbered, colored boxes. The TALEN-recognized sequences are shown as blue letters whereas the insertion sequences described as red letters. (B) Schematic diagram depicting the sequence of the CRISPR sgRNA-targeted region in wild type and TRb mutants (19 base-deletion or 29 base-deletion) animals. The protein coding exons are shown as numbered, colored boxes. The CRISPR short guide RNA (sgRNA)-recognized sequence is shown as red box (top) or red letters (below). Exon and intron sequences are shown in capital or lower-case letters, respectively. (C) Representative genotyping by PCR. Genotyping PCR was carried out on genomic DNA by using a common primer set, primer F and primer R. The presence of only upper (105 bp) or lower (86 bp) band in the gel indicates a wild type or homozygous mutant animal, respectively, while the presence of both upper and lower bands indicates a heterozygous mutant. (D) TR double knockout with a 29 base out-of-frame mutation in TRb locus (TRDKOD29) inhibits intestinal shortening at the climax of metamorphosis. The intestine length was measured and normalized against total body length at indicated stages. At least 4 tadpoles were analyzed for each sample. Asterisks (***) indicate a significant difference vs stage 58, for the 2 genotypes (P < 0.001).
	Supplemental Figure 1. [E] TR double knockout tadpoles with a homozygous 29 base-out-frame deletion (14 base in exon and 15 base in intron) of TRb gene locus shows similar intestinal remodeling defects as TR double knockout tadpoles with a homozygous 19 base-out-frame mutation of TRb gene locus. (continued) (E) Abnormal intestinal morphology in TRDKOD29 tadpoles. Cross-sections of the intestine isolated from tadpoles were stained with methyl green-pyronin Y . (a and b): TRa (+/+)TRb ( +/+) ; and (c and d): TRa (-/-)TRb (-/-)D29. Note the precocious folding of the epithelium in the TRDKOD29 tadpoles by as early as stage 58, similar as TRDKOD19 tadpoles (see text). T: typhlosole. Bars: 100 μm.
	Supplemental Figure 2. Validation of RNA-seq data for the upregulated genes. A number of up-regulated genes identified from the RNA-seq were selected for qRT- igure S2 PCR analysis. The results from the RNA-seq (left) and qRT-PCR (right) were all consistent. Shown here are the expression patterns for 4 representative genes, lum, TH/bzip, hbg1 and slc5a8. All expression data for RNA-seq and qRT-PCR were shown in FPKM and relatively expression normalized against that of rpl8, respectively.
	Supplemental Figure 3. Validation of RNA-seq data for the downregulated genes. A number of down-regulated genes identified from the RNA-seq were selected for qRT-PCR analysis. The results from the RNA-seq (left) and qRT-PCR (right) were all consistent. Shown here are the expression patterns for 3 representative genes, slc22a2, gatm and gstp1. All expression data for RNA-seq and qRT-PCR were shown in FPKM and relatively expression normalized against that of rpl8, respectively.
	Supplemental Figure 4. A representative Notch signaling pathway likely involved in the development of adult intestinal stem cells as revealed by RNA-seq analysis. Note that many more genes were upregulated (red) at stage 61 in the wild type tadpoles (Top) compared to the TRa (-/-)TRb (-/-) animals and the reverse was true for downregulated genes (green). The color bars for gene expression are in log2 scale.
	TOP PANEL for Supplemental Figure 5. A representative cell cycle signaling pathway likely involved in the proliferation of adult intestinal stem cells as revealed by RNA-seq analysis. Figure S4 Note that many more mitosis related genes (right side) and G2-related genes (middle right) were upregulated (red) at stage 61 in the wild type tadpoles (Top) compared to the TRa (-/-)TRb (-/-) animals. Conversely, many more downregulated genes (green) were present among the S- (middle left) and G2 (middle right)-related genes in the TRa (-/-)TRb (-/-) animals. G1: Gap 1 phase, S: S phase, G2: Gap2 phase and M: Mitosis. The color bars for gene expression are in log2 scale.
	Bpttom Panel of Supplemental Figure 5. A representative cell cycle signaling pathway likely involved in the proliferation of adult intestinal stem cells as revealed by RNA-seq analysis. Figure S4 Note that many more mitosis related genes (right side) and G2-related genes (middle right) were upregulated (red) at stage 61 in the wild type tadpoles (Top) compared to the TRa (-/-)TRb (-/-) animals. Conversely, many more downregulated genes (green) were present among the S- (middle left) and G2 (middle right)-related genes in the TRa (-/-)TRb (-/-) animals. G1: Gap 1 phase, S: S phase, G2: Gap2 phase and M: Mitosis. The color bars for gene expression are in log2 scale.

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