Thyroid hormone receptor alpha controls larval intestinal epithelial cell death by regulating the CDK1 pathway

Tanizaki et al use ChIP-Seq to identify over 3000 Thyroid hormone (T3) receptor (TR)-bound genes in the intestine of premetamorphic wild type Xenopus tropicalis tadpoles and in TR alpha-knockouts. They show that treatment of tadpoles with cell cycle inhibitors blocked T3-induced intestinal remodeling, suggesting that TR alpha-dependent activation of the cell cycle is important for T3-induced apoptosis during intestinal remodelling. Thyroid hormone (T3) regulates adult intestine development through T3 receptors (TRs). It is difficult to study TR function during postembryonic intestinal maturation in mammals due to maternal influence. We chose intestinal remodeling during Xenopus tropicalis metamorphosis as a model to study TR function in adult organ development. By using ChIP (chromatin immunoprecipitation)-Seq, we identified over 3000 TR-bound genes in the intestine of premetamorphic wild type or TR alpha (the major TR expressed during premetamorphosis)-knockout tadpoles. Surprisingly, cell cycle-related GO (gene ontology) terms and biological pathways were highly enriched among TR target genes even though the first major event during intestinal metamorphosis is larval epithelial cell death, and TR alpha knockout drastically reduced this enrichment. More importantly, treatment of tadpoles with cell cycle inhibitors blocked T3-induced intestinal remodeling, especially larval epithelial cell death, suggesting that TR alpha-dependent activation of cell cycle is important for T3-induced apoptosis during intestinal remodeling.