The thyroid hormone nuclear receptors and the Wnt/β-catenin pathway: An intriguing liaison

Skah, Seham; Uchuya-Castillo, Joel; Sirakov, M; Plateroti, Michelina

doi:10.1016/j.ydbio.2017.01.003

Cited by 42 publications

(39 citation statements)

References 182 publications

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“…Nevertheless, all of the groups significantly overexpressed THRA, and the most significant overexpression compared with normal tissues was observed in CMS2 and CMS3 (Figure 1A ). As mentioned above, these two groups are related to Wnt activity and with metabolic pathways, consistent with our previous results in mice on the association between TRα1 and Wnt [ 14 ] and with the well-known action of thyroid hormones/TRs on the metabolism [ 15 ]. Interestingly, in TCGA colorectal tumors, the levels of THRA expression were significantly and directly correlated with Wnt activity (Figure 1B ), once again reinforcing the link between TRα1 and the Wnt pathway.…”

Section: Resultssupporting

confidence: 91%

“…IPA also resulted in the identification of the most significant canonical pathways within the dataset ( Supplementary Figure 5B ). Interestingly, these were the Cdc42, which is related to cell division and cell cycle, and the Wnt/β-catenin pathway, previously correlated with the function of TRα1 [ 14 ]. To corroborate the microarray data, we used an RT-qPCR approach and validated most of the differentially expressed genes (DE) that belonged to the Wnt and Notch pathways, to nuclear hormone receptor signaling, or that were strongly regulated ( Supplementary Table 3 ).…”

Section: Resultsmentioning

confidence: 99%

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Increased expression of the thyroid hormone nuclear receptor TRα1 characterizes intestinal tumors with high Wnt activity

et al. 2018

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Our previous work demonstrated a key function of the thyroid hormone nuclear receptor TRα1, a T3-modulated transcription factor, in controlling intestinal development and homeostasis via the Wnt and Notch pathways. Importantly, increased expression of TRα1 in the intestinal epithelium in a mutated Apc genetic background (vil-TRα1/Apc+/1638N mice) accelerated tumorigenesis and contributed to a more aggressive tumor phenotype compared to that of the Apc mutants alone. Therefore, the aim of this study was to determine the relevance of this synergistic effect in human colorectal cancers and to gain insights into the mechanisms involved. We analyzed cohorts of patients by in silico and experimental approaches and observed increased TRα1 expression and a significant correlation between TRα1 levels and Wnt activity. TRα1 loss-of-function and gain-of-function in Caco2 cell lines not only confirmed that TRα1 levels control Wnt activity but also demonstrated the role of TRα1 in regulating cell proliferation and migration. Finally, upon investigation of the molecular mechanisms responsible for the Wnt-TRα1 association, we described the repression by TRα1 of several Wnt inhibitors, including Frzb, Sox17 and Wif1. In conclusion, our results underline an important functional interplay between the thyroid hormone nuclear receptor TRα1 and the canonical Wnt pathway in intestinal cancer initiation and progression. More importantly, we show for the first time that the expression of TRα1 is induced in human colorectal cancers.

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Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Increased expression of the thyroid hormone nuclear receptor TRα1 characterizes intestinal tumors with high Wnt activity

et al. 2018

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“…Interestingly, in the adult mammalian intestine, HA has been also shown to promote epithelial proliferation in the crypt including the stem cells that express LGR5 and CD44 . In addition, there is a growing body of evidence showing the cross‐talk between TH and the canonical Wnt pathway in mammalian organs including the intestine . Taken together, it is tempting to speculate that the TH‐upregulated HA/CD44 signaling plays evolutionarily conserved roles in regulation of the intestinal stem cells among vertebrates throughout postembryonic development and adult life.…”

Section: Resultsmentioning

confidence: 99%

Essential Roles of Thyroid Hormone-Regulated Hyaluronan/CD44 Signaling in Adult Stem Cell Development During Xenopus laevis Intestinal Remodeling

et al. 2017

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In the amphibian intestine during metamorphosis, thyroid hormone (TH) induces some larval epithelial cells to dedifferentiate into stem cells, which generate the adult epithelium analogous to the mammalian intestinal epithelium. We have previously shown that the canonical Wnt signaling pathway is involved in adult epithelial development in the Xenopus laevis intestine. To understand the function of this pathway more precisely, we here focused on CD44, a major Wnt target, which has been identified as a TH response gene in the X. laevis intestine. Our in situ hybridization analysis indicated that CD44 mRNA is detectable in adult epithelial primordia consisting of the adult stem/progenitor cells and is strongly expressed in the connective tissue (CT) cells surrounding them. Interestingly, when the expression of CD44 mRNA is the highest, hyaluronan (HA), a principle ligand of CD44, is newly synthesized and becomes most abundantly distributed in the CT just beneath the adult epithelial primordia that are actively proliferating. Thereafter, as the adult primordia differentiate into the simple columnar epithelium, the expression of CD44 mRNA is gradually downregulated. More importantly, using organ cultures of the X. laevis tadpole intestine in the presence of TH, we have experimentally shown that inhibition of HA synthesis by 4-methylumbelliferone suppresses development of not only the CT but also the epithelial stem cells, resulting in failure to generate the AE. Our findings strongly suggest that TH-upregulated HA/CD44 signaling plays an essential role in formation of the intestinal stem cell niche during vertebrate postembryonic development. Stem Cells 2017;35:2175-2183.

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“…In the NOTCH and Hedgehog sub-pathways MTHs regulated genes in almost all reactions, while in the WNT sub-pathways MTH regulated genes were more variable. WNT signalling 42 has previously been linked to THs but less is known about the role of THs in the NOTCH pathway. In fact C17 cells expressing Trha or Trhb 36 or primary mouse cerebrocortical cells treated with T3 37 revealed up-regulation of the Notch1 and 4 receptor, Jag1, Hr and Hes6 expression, whereas in the zebrafish MCT8 morphants all these genes were down-regulated.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomics reveal an integrative role for maternal thyroid hormones during zebrafish embryogenesis

Silva

Louro

Trindade

et al. 2017

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Thyroid hormones (THs) are essential for embryonic brain development but the genetic mechanisms involved in the action of maternal THs (MTHs) are still largely unknown. As the basis for understanding the underlying genetic mechanisms of MTHs regulation we used an established zebrafish monocarboxylic acid transporter 8 (MCT8) knock-down model and characterised the transcriptome in 25hpf zebrafish embryos. Subsequent mapping of differentially expressed genes using Reactome pathway analysis together with in situ expression analysis and immunohistochemistry revealed the genetic networks and cells under MTHs regulation during zebrafish embryogenesis. We found 4,343 differentially expressed genes and the Reactome pathway analysis revealed that TH is involved in 1681 of these pathways. MTHs regulated the expression of core developmental pathways, such as NOTCH and WNT in a cell specific context. The cellular distribution of neural MTH-target genes demonstrated their cell specific action on neural stem cells and differentiated neuron classes. Taken together our data show that MTHs have a role in zebrafish neurogenesis and suggest they may be involved in cross talk between key pathways in neural development. Given that the observed MCT8 zebrafish knockdown phenotype resembles the symptoms in human patients with Allan-Herndon-Dudley syndrome our data open a window into understanding the genetics of this human congenital condition.

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The thyroid hormone nuclear receptors and the Wnt/β-catenin pathway: An intriguing liaison

Cited by 42 publications

References 182 publications

Increased expression of the thyroid hormone nuclear receptor TRα1 characterizes intestinal tumors with high Wnt activity

Increased expression of the thyroid hormone nuclear receptor TRα1 characterizes intestinal tumors with high Wnt activity

Essential Roles of Thyroid Hormone-Regulated Hyaluronan/CD44 Signaling in Adult Stem Cell Development During Xenopus laevis Intestinal Remodeling

Transcriptomics reveal an integrative role for maternal thyroid hormones during zebrafish embryogenesis

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