Unliganded thyroid hormone receptor function: amphibian metamorphosis got TALENs.

Thyroid hormones (THs) are capital for development and cell homeostasis. THs act by regulating gene expression through TH receptors (TRs), which are transcription factors that belong to the nuclear receptors superfamily (1). THs and TRs are versatile players because they can not only up-regulate, but also down-regulate, gene expression in target cells. It is generally believed that TRs mediate both effects with their ability to bind DNA, regardless of the presence of its ligand. Unfortunately, the details of the mechanisms involved in transcriptional repression by THs remain enigmatic. However, most studies have focused on the mechanism of TR action on up-regulated TH-response genes. In brief, TRs repress the transcription in the absence of THs, whereas TRs lead to gene activation in the presence of THs. The fact that unliganded TR seems to work as an active repressor raises one main question. For instance, what is the physiological role of this active repression through unliganded TR? Only few developmental roles of unliganded TRs have been described in mammals despite TRs expression when TH levels are absent or minimal (2). This physiological status is encountered during pregnancy when the thyroid gland is not yet functional. In this case, unliganded TRs may serve as a competence factors that enable tissues to respond upon TH release later. However, this is difficult to observe in mammals because THs may pass through the placenta, and thus, low levels of THs are present in the fetus. Low/no TH availability also occurs through the modulation of deiodinases activity in target cells (3). Deiodinases are enzymes involved in the activation of TH precursor but also in TH degradation that force the accumulation of unliganded TRs. The roles of unliganded TRs are not fully defined yet. Alternative models can then be attractive. The Anura amphibians are a pertinent choice. In this issue of Endocrinology, two manuscripts from Wen and Shi (4) and Choi et al (5) present elegant works that manages to address the aforementioned question in amphibians. Anura development is indirect with embryogenesis and adult stages separated by a larval period (corresponding to tadpole growth) that end with metamorphosis. Metamorphosis is a spectacular postembryonic transition. This developmental phase, which is strictly triggered by THs, corresponds to the perinatal period in mammals or to hatching in sauropsids, periods also marked by high levels and strong action of THs (6). In amphibians, a dual-function model for TR during development was proposed (7). In premetamorphic tadpoles in which TRs are expressed and TH levels are barely detectable, unliganded TRs represses transcription of target genes. During metamorphosis, endogenous THs allow TRs to activate gene expression, which leads to tadpole transformation. Although this model is strongly supported by mechanistic evidences (7), the in vivo function of unliganded TRs in the premetamorphic tadpoles is unknown. The work of Wen and Shi (4) and Choi et al (5) using a powerful promising technology clearly reach a breakthrough. New genome editing technologies are popular tools to dissect developmental mechanism in a wide variety of organisms. Xenopus is a classical model widely used in the study of development, but its usefulness has been strongly limited by the lack of genetic tools (homologous recombination and embryonic stem cell derivation) that prevent gene targeting. Currently transcription activator-like effector nucleases (TALENs) have become effective tools for target gene editing/knockout in Xenopus (8). TALENs are