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

Abstract

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 TRα in gene repression and developmental timing using tadpoles of TRα knockout (TRαKO) frogs. Here, we examined the role of liganded TRα on growth, development, and intestinal remodeling during natural and TH-induced metamorphosis. Disrupted TRα had little effect on growth during the larval period, but after metamorphosis, TRαKO juveniles grew more slowly than wild-type (WT) juveniles. TRαKO tadpoles developed faster throughout premetamorphosis when TH was low or absent, and despite their decreased responsivity to exogenous TH, TRαKO 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 TRαKO tadpoles. Also, TRαKO intestines did not shrink in length to the full extent, and fewer intestinal folds into the lumen were present in TRαKO compared with WT juveniles. Such delayed remodeling occurred despite higher premetamorphic expression levels of TH target genes important for metamorphic progression-namely, TRβ, 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 TRα null mouse model, TRαKO frogs had statistically significant but surprisingly mild growth and development phenotypes with normal survival and fertility.