Abstract
Thyroid hormone (T3) receptors (TRs) mediate T3 effects on vertebrate development. We have studied Xenopus tropicalis metamorphosis as a model for postembryonic human development and demonstrated that TRα knockout induces precocious hind limb development. To reveal the molecular pathways regulated by TRα during limb development, we performed chromatin immunoprecipitation- and RNA-sequencing on the hind limb of premetamorphic wild type and TRα knockout tadpoles, and identified over 700 TR-bound genes upregulated by T3 treatment in wild type but not TRα knockout tadpoles. Interestingly, most of these genes were expressed at higher levels in the hind limb of premetamorphic TRα knockout tadpoles than stage-matched wild-type tadpoles, suggesting their derepression upon TRα knockout. Bioinformatic analyses revealed that these genes were highly enriched with cell cycle and Wingless/Integrated (Wnt) signaling-related genes. Furthermore, cell cycle and Wnt signaling pathways were also highly enriched among genes bound by TR in wild type but not TRα knockout hind limb. These findings suggest that direct binding of TRα to target genes related to cell cycle and Wnt pathways is important for limb development: first preventing precocious hind limb formation by repressing these pathways as unliganded TR before metamorphosis and later promoting hind limb development during metamorphosis by mediating T3 activation of these pathways.
Highlights
Thyroid hormone (T3) is essential for organ metabolism and animal development in all vertebrates, especially during postembryonic development, a period around birth in mammals when plasma T3 level reaches the peak [1,2,3,4]
When Gene Ontology (GO) analysis was performed on these 3714 T3 receptors (TRs)-bound genes, we observed that the GO terms related to the development and cellular processes such as cell cycle were among the most significantly enriched GO terms (Figure 1B, Supplemental Table S4)
As TRα knockout slows down the limb development durin metamorphosis when T3 is present, these findings suggest an importa role of TRα in mediating T3 signal to activate cell cycle genes to promote cell cycle pr gression in hind limb development during metamorphosis between stage 548 oafn1d8 stage 5 when limb development is essentially complete
Summary
Thyroid hormone (T3) is essential for organ metabolism and animal development in all vertebrates, especially during postembryonic development, a period around birth in mammals when plasma T3 level reaches the peak [1,2,3,4]. During this period, many organs, including the intestine and brain, are drastically remodeled to the adult form with distinct morphology compared to the fetal organs [5]. In the absence of T3, these complexes recruit corepressors such as nuclear receptor corepressor (N-CoR) and silencing mediator of retinoid and thyroid hormone receptor (SMRT) and reduce histone acetylation. The main reason is the difficulty of studying mammalian embryos and neonates that depend on maternal supply for survival
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