Thyroid Hormones Regulate Goblet Cell Differentiation and Fgf19-Fgfr4 Signaling
Thyroid Hormones Regulate Goblet Cell Differentiation and Fgf19-Fgfr4 Signaling
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DOI：
10.1210/endocr/bqab047
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发表时间：
2021-03-01
期刊：
影响因子：
4.8
通讯作者：
Appelbaum, Lior
中科院分区：
文献类型：
--
作者：
Blitz, Einat;Matsuda, Hiroki;Appelbaum, Lior
甲状腺功能减退症是一种常见的病理状态，其特征是甲状腺激素(TH)、甲状腺激素(T4)和3，5，3‘-三碘甲状腺原氨酸(T3)在全身或特定组织中活性不足。甲状腺功能减退症与肠道发育不足以及胃肠道疾病有关。我们使用甲减的斑马鱼模型来识别和表征控制肠道发育的TH调节基因和细胞通路。在甲状腺功能低下的青少年和成人的肠道中，分泌粘液的杯状细胞的数量减少，这一表型可被T3处理所挽救。转录组图谱显示，与对照组相比，甲状腺功能低下成年人的肠道中有数十个差异表达基因。值得注意的是，编码FGF19及其受体FGFR4的基因在甲状腺功能低下的成人肠道中的表达显著增加，而T3治疗使其正常化。阻断成纤维细胞生长因子(FGF)信号，使用可诱导的显性-阴性FGFR转基因系，挽救了甲状腺功能低下成年人的杯状细胞数量。这些结果表明，THs抑制FGF19-FGFR4信号通路，这与抑制甲状腺功能减退症的杯状细胞分化有关。TH和FGF19-FGFR4信号通路均可作为治疗TH相关胃肠道疾病的药物靶点。
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.