The thyroid hormone receptor TRalpha1 regulates intestinal development and homeostasis by controlling epithelial proliferation in the crypts. This involves positive control of the Wnt/beta-catenin pathway. To further investigate the effect of thyroid hormone-TRalpha1 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 TRalpha1 and that it activates beta-catenin signaling via Frizzled receptors. Indeed, sFRP2 stabilizes beta-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 TRalpha1 and components of the Wnt/beta-catenin pathway. Moreover, we describe in this study a novel mechanism of action of sFRP2, responsible for the activation of beta-catenin signaling.