The Frizzled-related sFRP2 Gene Is a Target of Thyroid Hormone Receptor α1 and Activates β-Catenin Signaling in Mouse Intestine

Abstract

The thyroid hormone receptor TR␣1 regulates intestinal development and homeostasis by controlling epithelial proliferation in the crypts. This involves positive control of the Wnt/␤-catenin pathway. To further investigate the effect of thyroid hormone-TR␣1 signaling on the intestinal epithelium proliferating compartment, we performed a comparative transcription profile analysis on laser microdissected crypt cells recovered from wild type animals with normal or perturbed hormonal status, as well as from TR knock-out mice. Statistical analysis and an in silico approach allowed us to identify 179 differentially regulated genes and to group them into organized functional networks. We focused on the "cell cycle/cell proliferation" network and, in particular, on the Frizzled-related protein sFRP2, whose expression was greatly increased in response to thyroid hormones. In vitro and in vivo analyses showed that the expression of sFRP2 is directly regulated by TR␣1 and that it activates ␤-catenin signaling via Frizzled receptors. Indeed, sFRP2 stabilizes ␤-catenin, activates its target genes, and enhances cell proliferation. In conclusion, these new data, in conjunction with our previous results, indicate a complex interplay between TR␣1 and components of the Wnt/␤-catenin pathway. Moreover, we describe in this study a novel mechanism of action of sFRP2, responsible for the activation of ␤-catenin signaling.

Cathepsin H regulated by the thyroid hormone receptors associate with tumor invasion in human hepatoma cells

“…However, elucidation of the underlying mechanisms by which T 3 regulated requires further study. Previous reports have shown that TRs are potent inducer of tumorigenesis (Plateroti et al, 2006;Chen et al, 2008a;Kress et al, 2009). In this study, we report that the T 3 /TR controls the transcription of the CTSH gene and that T 3 -mediated cell migration appears to involve CTSH.…”

“…Thyroid hormone and TRa1 control epithelial cell proliferation and the expression of components of the Wnt pathway (Plateroti et al, 2006). The expression of the b-catenin and sFRP2 gene is regulated directly by TRa1, and the Wnt/ b-catenin signaling networks contribute to intestinal tumorigenesis (Kress et al, 2009). Chiloeches et al (2008) reported that ERK but not c-Jun N-terminal kinase or p38-MAPK is activated on exposure to T 3 in rat pituitary tumor (GH4C1) cells.…”

Thyroid hormones and the control of cell proliferation or cell differentiation: Paradox or duality?

“…This finding is very consistent with the diversified responses to THs among different organs during metamorphosis. It is worth noting that by comparing this study with the one by Kress et al (Kress et al, 2009), it is possible to reveal a consistent number of common target genes in the developing intestine of both Xenopus and mouse.…”

“…This function depends on the TR 1 receptor Plateroti et al, 2001;Flamant et al, 2002) and involves the transcriptional regulation of cell cycle control genes and of the Wnt/ -catenin pathway (Plateroti et al, 2006;Kress et al, 2009) (detailed in the next paragraph);…”

“…In order to analyze the THs-responsive genes in more detail, we used a global comparative transcription profile approach on laser microdissected intestinal crypt cells from animals before they were weaned. This approach allowed us not only to compile a comprehensive list of target genes in these cells, but also to define the crosstalk between THs-TRα1 and other signaling pathways that control epithelial cell homeostasis (Kress et al, 2009). One of the major results described in this analysis was the characterization of a new direct target of TRα1, the secreted frizzled-related protein sFRP2, which is another component of the Wnt/β-catenin pathway (rev.…”