Growth, Development, and Intestinal Remodeling Occurs in the Absence of Thyroid Hormone Receptor α in Tadpoles of Xenopus tropicalis

During development in all vertebrates, thyroid hormone receptors (TRs) are expressed before as well as during and after the peak in plasma thyroid hormone (TH) levels. Previously, we established a role for unliganded TR alpha in gene repression and developmental timing using tadpoles of TR alpha knockout (TR alpha KO) frogs. Here, we examined the role of liganded TR alpha on growth, development, and intestinal remodeling during natural and TH-induced metamorphosis. Disrupted TR alpha had little effect on growth during the larval period, but after metamorphosis, TR alpha KO juveniles grew more slowly than wild-type (WT) juveniles. TR alpha KO tadpoles developed faster throughout premetamorphosis when TH was low or absent, and despite their decreased responsivity to exogenous TH, TR alpha KO tadpoles not only were able to complete TH-dependent metamorphosis but also did so earlier than WT tadpoles. In contrast to external morphology, larval epithelial cell apoptosis and adult cell proliferation of intestinal remodeling were delayed in TR alpha KO tadpoles. Also, TR alpha KO intestines did not shrink in length to the full extent, and fewer intestinal folds into the lumen were present in TR alpha KO compared with WT juveniles. Such delayed remodeling occurred despite higher premetamorphic expression levels of TH target genes important for metamorphic progression-namely, TR beta, Klf9, and ST3. Furthermore, the decreased TH-dependent intestinal shrinkage was consistent with reduced TH response gene expression during natural and TH-induced metamorphosis. As in the TR alpha null mouse model, TR alpha KO frogs had statistically significant but surprisingly mild growth and development phenotypes with normal survival and fertility.