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

Yuki Shibata,Hongen Zhang,Yun-Bo Shi,Mary Dasso,Hangnoh Lee,Yuta Tanizaki

doi:10.3390/cells10030536

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.

Highlights

Plasma thyroid hormone (T3) levels reach a peak around birth, known as the postembryonic period, during human development, when many organs/tissues such as intestine mature into their adult forms
When we carried out Gene ontology (GO) analyses of genes that were regulated between stage 54 and stage 61 in WT animals, we found that genes in the GO categories such as cell adhesion/extracellular matrix (ECM) organization, cell cycle/proliferation, stem cells, etc., were enriched among the up-regulated genes, while those associated with GO categories such as translational initiation, translation, rRNA processing, and nuclear-transcribed mRNA catabolic processes, nonsense-mediated decay, etc., were significantly enriched among the downregulated genes (Table S8)
Our findings here have revealed an essential role of thyroid hormone receptors (TRs) for intestinal remodeling during anuran metamorphosis

Summary

Introduction

Plasma thyroid hormone (T3) levels reach a peak around birth, known as the postembryonic period, during human development, when many organs/tissues such as intestine mature into their adult forms. Anuran metamorphosis is the most dramatic morphological transformation regulated by T3 but without maternal influence. The effect of T3 is mediated mainly through transcriptional regulation via thyroid hormone receptors (TRs), which form heterodimers with retinoic X receptors (RXRs) and recruit cofactor complexes such as those containing steroid receptor coactivators (SRCs) or protein arginine methyltransferase 1 (PRMT1) to target genes [5,9,10,11,12,13,14]. In vertebrates including pseudo-tetraploid species Xenopus laevis and diploid species Xenopus tropicalis, two TR genes, TRα and TR®, exist and have distinct spatiotemporal expression patterns

Methods

Discussion

Conclusion