Thyroid Hormone Receptor Is Essential for Larval Epithelial Apoptosis and Adult Epithelial Stem Cell Development but Not Adult Intestinal Morphogenesis during Xenopus tropicalis Metamorphosis

Abstract

Vertebrate postembryonic development is regulated by thyroid hormone (T3). Of particular interest is anuran metamorphosis, which offers several unique advantages for studying the role of T3 and its two nuclear receptor genes, TRα and TRβ, during postembryonic development. We have recently generated TR double knockout (TRDKO) Xenopus tropicalis animals and reported that TR is essential for the completion of metamorphosis. Furthermore, TRDKO tadpoles are stalled at the climax of metamorphosis before eventual death. Here we show that TRDKO intestine lacked larval epithelial cell death and adult stem cell formation/proliferation during natural metamorphosis. Interestingly, TRDKO tadpole intestine had premature formation of adult-like epithelial folds and muscle development. In addition, T3 treatment of premetamorphic TRDKO tadpoles failed to induce any metamorphic changes in the intestine. Furthermore, RNA-seq analysis revealed that TRDKO altered the expression of many genes in biological pathways such as Wnt signaling and the cell cycle that likely underlay the inhibition of larval epithelial cell death and adult stem cell development caused by removing both TR genes. Our data suggest that liganded TR is required for larval epithelial cell degeneration and adult stem cell formation, whereas unliganded TR prevents precocious adult tissue morphogenesis such as smooth-muscle development and epithelial folding.

Thyroid Hormone Nuclear Receptor TRα1 and Canonical WNT Pathway Cross-Regulation in Normal Intestine and Cancer

“…In the case of the normal mucosae of vil-TRa1/Apc mice, the molecular phenotype is even more intriguing, given that these portions of the intestines have histological appearance similar to that of the vil-TRa1, but show molecular features close to the tumors. According to the literature and also considering our work, THs-TRs definitively play a pivotal role in intestinal development and homeostasis in both mouse and amphibians by regulating the expression of a large panel of genes, including those belonging to the WNT pathway and cell cycle regulators (37,53,54). It is important to underline that all these studies provide data that can be now used in bioinformatics and statistics analyses for a direct comparison of TH-TR dependent mechanisms in the intestine of different species.…”

Proteomic Analysis of the Intestinal Resistance to Thyroid Hormone Mouse Model With Thyroid Hormone Receptor Alpha Mutations

“…Wen L et al and Choi J et al reported that T 3 and TRα have indispensable roles during the intestinal remodeling of amphibian metamorphosis ( 25 , 26 ). Thra -/- and Thra -/- Thrb -/- (TR double knockout) mutations in Xenopus tropicalis were shown to result in reduced larval epithelial cell apoptosis and reduced adult stem cell formation/proliferation during metamorphosis ( 27 , 28 ). Similarly, cell proliferation in the crypt was found to be reduced in both Thra knockout mice and Pax8 -/- mice ( 19 , 20 , 29 ).…”

Interdependence of Thyroid and Corticosteroid Signaling in Vertebrate Developmental Transitions

“…This result supports the role of unliganded TR to avoid precocious metamorphosis for proper tadpole growth. Finally, removal of TR prevents the disappearance of tadpole-specific tissues (Shibata et al, 2020(Shibata et al, , 2021.…”