Thyroid Hormones Regulate Goblet Cell Differentiation and Fgf19-Fgfr4 Signaling

Hypothyroidism is a common pathological condition characterized by insufficient activity of the thyroid hormones (THs), thyroxine (T4), and 3,5,3'-triiodothyronine (T3), in the whole body or in specific tissues. Hypothyroidism is associated with inadequate development of the intestine as well as gastrointestinal diseases. We used a zebrafish model of hypothyroidism to identify and characterize TH-modulated genes and cellular pathways controlling intestine development. In the intestine of hypothyroid juveniles and adults, the number of mucus-secreting goblet cells was reduced, and this phenotype could be rescued by T3 treatment. Transcriptome profiling revealed dozens of differentially expressed genes in the intestine of hypothyroid adults compared to controls. Notably, the expression of genes encoding to Fgf19 and its receptor Fgfr4 was markedly increased in the intestine of hypothyroid adults, and treatment with T3 normalized it. Blocking fibroblast growth factor (FGF) signaling, using an inducible dominant-negative Fgfr transgenic line, rescued the number of goblet cells in hypothyroid adults. These results show thatTHs inhibit the Fgf19-Fgfr4 signaling pathway, which is associated with inhibition of goblet cell differentiation in hypothyroidism. Both the TH and Fgf19-Fgfr4 signaling pathways can be pharmaceutical targets for the treatment of TH-related gastro-intestinal diseases.

Automated summary

Hypothyroidism is characterized by insufficient thyroid hormone activity, leading to reduced goblet cells in the intestine, which can be rescued by T3 treatment. Transcriptome profiling revealed differential gene expression in the intestine of hypothyroid adults, with Fgf19-Fgfr4 signaling pathway being associated with inhibition of goblet cell differentiation in hypothyroidism. Targeting the TH and Fgf19-Fgfr4 signaling pathways could be a potential treatment for TH-related gastro-intestinal diseases.