Regulation of growth rate and developmental timing by Xenopus thyroid hormone receptor α

Abstract

Thyroid hormone (TH) is critical for vertebrate postembryonic development, a period around birth in mammals when plasma TH levels are high. Interestingly, TH receptors (TRs), especially TRa, are expressed prior to the synthesis and secretion of zygotic TH, suggesting the existence of unliganded TR during development. However, the role of unliganded TR during mammalian development has been difficult to study, in part due to the relatively weak phenotype of TR knockout mice. Amphibian metamorphosis resembles postembryonic development in mammals and is controlled by TH via TRs. Like in mammals, TRa gene is highly activated and is the major TR expressed prior to the synthesis of endogenous TH. By using TALEN (transcriptional activator like effector nucleases)-mediated gene editing approach, we and others have now shown that unliganded TRa has two independent functions during Xenopus premetamorphosis, i.e. inhibiting growth rate and slowing development. Furthermore, molecular and transgenic studies have shown that unliganded TRa accomplishes these via the recruitment of histone deacetylase (HDAC)-containing corepressor complexes to repress the expression of TH-inducible genes.

A direct and widespread role for the nuclear receptor EcR in mediating the response to ecdysone inDrosophila

“…Hormones and other small molecules act through nuclear receptors to initiate transcriptional cascades that often continue for extended periods of time. For example, thyroid hormone triggers metamorphosis in frogs and other chordates, a process that can take weeks for completion (60). Our work raises the possibility that nuclear receptors play an extensive and direct role in regulating activity of downstream response genes.…”

Long term effects of carbaryl exposure on antiviral immune responses in Xenopus laevis

“…Amphibian metamorphic development is controlled by the thyroid hormone (reviewed in [35]), although little is known about hormonal control of the immune system transition besides MHC class I and II genes (reviewed in [36]). The possibility that carbaryl can affect leukocyte development is also consistent with the observed effect of carbaryl at a higher (10 μg/L or 10 ppb) dose, which considerably shortens the time to metamorphic completion.…”

Thyroid hormone receptor beta is critical for intestinal remodeling during Xenopus tropicalis metamorphosis

“…Interestingly, limited studies on the intestine, an internal organ, have revealed relative minor effects of TRα or TRβ knockout during natural metamorphosis, mainly a delay in intestinal remodeling relative to the external morphological changes in the knockout tadpoles [56][57][58][59]. This seems to contrast with the strong upregulation of TRβ during intestinal metamorphosis in both Xenopus laevis and Xenopus tropicalis [36,54,55], two related anuran species that undergo very similar intestinal remodeling [38,47]. It is possible that the relatively minor effects observed for the TR knockouts during natural intestinal metamorphosis is in part due to comparing wild type and knockout animals of different ages (in order to match the stage) and/or due to distinct, developmental stage-dependent effects of the TR knockouts on the intestine and external organs that are used to determine the stages of the animals.…”

“…We have been studying amphibian metamorphosis as a model system for understanding the regulation of postembryonic vertebrate adult organ development by T3. During metamorphosis in anurans such as the pseudo-tetraploid Xenopus laevis and its highly related diploid species Xenopus tropicalis, T3 induces dramatic tissue modifications in essentially all tissues/organs [3,4,[32][33][34][35][36]. Of particular interest among them is intestinal remodeling.…”

“…Interestingly, when analyzed in the intestine or whole tadpoles, TRα is expressed at high levels from premetamorphosis to the end of metamorphosis while TRβ expression is low during premetamorphosis but is induced as a direct T3 target gene to peak at the climax of metamorphosis [36,[52][53][54][55]. Consistently, gene knockout studies in Xenopus tropicalis have shown that TRα single knockout accelerates premetamorphic tadpole growth and development (based on hindlimb morphology), likely due to the removal of unliganded TRα which leads to depression of T3 target genes [56,57].…”