The thyroid hormones and their nuclear receptors in the gut: From developmental biology to cancer

Abstract

The thyroid hormones control the development and the homeostasis of several organs in vertebrates. Their actions depend, for the most part, on nuclear receptors, the TRs, which are transcription factors whose activity is modulated by the hormone T3. The gastrointestinal tract is a well characterized target of thyroid hormones and TRs, as extensively described in the literature. In fact, its remodeling in amphibians during thyroid hormone-dependent metamorphosis is well characterized at the cellular and the molecular levels. However, whereas a great attention has been paid to the nervous system and to cardiac development and physiology, the function of thyroid hormones and TRs in the mammalian gastrointestinal tract has been, until recently, underestimated. Several studies have described an important conservation of this hormonal signal during intestinal development and have suggested that it may play a role in stem cell physiology in both amphibians and mammals. These findings show the importance of the thyroid hormones and TRs, whose homologous actions are maintained across species. In the present review, we summarize the most recent data on this issue, starting from work that has been conducted on amphibian metamorphosis to results on postnatal development, homeostasis, and tumorigenesis in mammals. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.

The thyroid hormone nuclear receptor TRα1 controls the Notch signaling pathway and cell fate in murine intestine

“…Its development and homeostasis involve several signaling pathways, including Wnt, Hedgehog, Notch, BMP and thyroid hormones (THs) (reviewed by Sirakov and Plateroti, 2011;van der Flier and Clevers, 2009). By cross-regulating each other, these pathways maintain the balance in physiological conditions among key biological processes such as proliferation, differentiation and apoptosis.…”

“…Importantly, their dysregulation is correlated with the induction and/or progression of pathologies such as colorectal cancer (Fre et al, 2009;Sirakov et al, 2012;Kress et al, 2010; reviewed by Radtke et al, 2006). TH signaling is a key regulator of gastrointestinal development and homeostasis in both amphibians and mammals, where it regulates postnatal development (reviewed by Sirakov and Plateroti, 2011;Shi et al, 2011). THs act via the thyroid hormone nuclear receptors (TRs), which belong to the nuclear hormone receptor transcription factor superfamily (reviewed by Robinson-Rechavi et al, 2003) and are modulated in their activity by the hormone triiodothyronine (T3) (reviewed by Chin and Yen, 1996;Oetting and Yen, 2007).…”

Maternal-Fetal Thyroid Interactions

“…This process is under the control of the circulating TH levels through negative feedback loops of this axis [28]. The availability of the active ligand T3 within tissues is locally determined by the action of the iodothyronine deiodinases (Ds) [29].…”

“…The synthesis of THs is regulated through the hypothalamus-pituitary-thyroid (HPT) axis [28] and the follicular cells of the thyroid gland synthesize and secrete T4 and T3 [1,2,21]. This process is under the control of the circulating TH levels through negative feedback loops of this axis [28].…”

“…Negative TREs (nTRE) can mediate ligand-dependent transcriptional repression, although in this case the role of coactivators and corepressors is not well defined [73,85]. TRs can also regulate the activity of genes that do not contain a TRE through "cross-talk" with other transcription factors (TF) that stimulate target gene expression [28,86]. Both receptors and coregulators are targets for phosphorylation (P) by signal transduction pathways stimulated by hormones and growth factors [84,85].…”