Regulation of stem cell development during tissue remodeling

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

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Abstract

SPERM ASSOCIATED ANTIGEN 7 IS ACTIVATED BY TH DURING XENOPUS TROPICALIS METAMORPHOSIS VIA A THYROID HORMONE RESPONSE ELEMENT WITHIN THE FIRST INTRON. TH We have previously identified sperm associated antigen 7 (spag7) as a candidate TH target gene that is potentially involved in adult stem cell development and/or proliferation during intestinal metamorphosis. To investigate whether TH regulates spag7 directly at the transcriptional level via TR, we first conducted qRT-PCR to analyze its expression during natural and TH-induced metamorphosis and found that spag7 was up-regulated during natural metamorphosis in the intestine, tail, brain and hindlimb, peaking at the climax of metamorphosis in all those organs, and upon TH treatment of premetamorphic tadpoles. Next, we demonstrated that an intronic TRE in spag7, first identified through bioinformatic analysis, could bind to TR in vitro and in vivo during metamorphosis. A dual luciferase assay utilizing a reconstituted frog oocyte transcription system showed that the TRE could mediate promoter activation by liganded TR. These results indicate that spag7 expression is directly regulated by TH through the TRE in the first intron during metamorphosis, implicating a role for spag7 early during TH-regulated tissue remodeling and resorption. THYROID HORMONE RECEPTOR CONTROLS LARVAL INTESTINAL EPITHELIAL CELL DEATH BY REGULATING THE CDK1 PATHWAY. We have been studying 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 (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 knockout drastically reduced this enrichment. More importantly, treatment of tadpoles with cell cycle inhibitors blocked TH-induced intestinal remodeling, especially larval epithelial cell death, suggesting that TR-dependent activation of cell cycle is important for TH-induced apoptosis during intestinal remodeling.