The Faculty of Life Sciences and the Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan, 5290002, Israel.
Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, 61231, Bad Nauheim, Germany.
Endocrinology. 2021 May 1;162(5). doi: 10.1210/endocr/bqab047.
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 that THs 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 gastrointestinal diseases.
甲状腺功能减退症是一种常见的病理状况，其特征是全身或特定组织中甲状腺激素（THs）、甲状腺素（T4）和 3,5,3'-三碘甲状腺原氨酸（T3）的活性不足。甲状腺功能减退症与肠道发育不良以及胃肠道疾病有关。我们使用甲状腺功能减退症的斑马鱼模型来鉴定和描述控制肠道发育的 TH 调节基因和细胞途径。在甲状腺功能减退的青少年和成年斑马鱼的肠道中，分泌粘液的杯状细胞数量减少，而 T3 处理可以挽救这种表型。转录组谱分析显示，与对照组相比，甲状腺功能减退的成年斑马鱼肠道中有数十个差异表达的基因。值得注意的是，编码 Fgf19 及其受体 Fgfr4 的基因在甲状腺功能减退的成年斑马鱼肠道中的表达明显增加，而 T3 处理使其正常化。使用可诱导的显性负性 Fgfr 转基因系阻断成纤维细胞生长因子（FGF）信号通路，可挽救甲状腺功能减退的成年斑马鱼中杯状细胞的数量。这些结果表明，TH 抑制 Fgf19-Fgfr4 信号通路，这与甲状腺功能减退症中杯状细胞分化的抑制有关。TH 和 Fgf19-Fgfr4 信号通路都可以成为治疗与 TH 相关的胃肠道疾病的药物靶点。
