TSH Receptor Function Is Required for Normal Thyroid Differentiation in Zebrafish
TSH Receptor Function Is Required for Normal Thyroid Differentiation in Zebrafish
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DOI：
10.1210/me.2011-0046
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发表时间：
2011-09-01
影响因子：
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通讯作者：
Costagliola, Sabine
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文献类型：
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作者：
Opitz, Robert;Maquet, Emilie;Costagliola, Sabine
TSH是甲状腺功能的主要生理调节剂。TSH对甲状腺细胞的作用是通过激活其膜受体[TSH受体（TSHR）]介导的。在这项研究中，我们研究了斑马鱼甲状腺功能分化和甲状腺器官发生过程中TSHR信号的作用。编码斑马鱼Tshr的cDNA的克隆显示了斑马鱼和哺乳动物TSHR之间一级结构和功能特性的保守性。原位杂交证实斑马鱼发育过程中甲状腺是tshr表达的主要部位。此外，我们确定TPO，IYD，DUOX和DUOXA作为斑马鱼甲状腺分化的新标记。分化标志物表达的时间分析表明，诱导早期甲状腺分化程序沿着甲状腺出芽，随后duox和duoxa表达与甲状腺激素合成同步延迟。此外，在小鼠和斑马鱼中的比较分析首次揭示了在早期甲状腺形态发生期间B细胞淋巴瘤2家族的细胞死亡调节因子的甲状腺富集表达。通过显微注射吗啡到胚胎中敲除tshr功能并不影响早期甲状腺形态发生，但在以后的功能分化中引起缺陷。在tshr变体中观察到的甲状腺表型在后期阶段包括功能性卵泡的数量和大小减少，分化标记物下调，以及甲状腺转录因子表达减少。我们的研究结果与在TSHR和cAMP信号传导缺陷的小鼠模型中观察到的表型的比较突出了斑马鱼作为模型的价值，以提高对脊椎动物甲状腺功能分化的理解。（分子内分泌学25：1579-1599，2011）
TSH is the primary physiological regulator of thyroid gland function. The effects of TSH on thyroid cells are mediated via activation of its membrane receptor [TSH receptor (TSHR)]. In this study, we examined functional thyroid differentiation in zebrafish and characterized the role of TSHR signaling during thyroid organogenesis. Cloning of a cDNA encoding zebrafish Tshr showed conservation of primary structure and functional properties between zebrafish and mammalian TSHR. In situ hybridization confirmed that the thyroid is the major site of tshr expression during zebrafish development. In addition, we identified tpo, iyd, duox, and duoxa as novel thyroid differentiation markers in zebrafish. Temporal analyses of differentiation marker expression demonstrated the induction of an early thyroid differentiation program along with thyroid budding, followed by a delayed onset of duox and duoxa expression coincident with thyroid hormone synthesis. Furthermore, comparative analyses in mouse and zebrafish revealed for the first time a thyroid-enriched expression of cell death regulators of the B-cell lymphoma 2 family during early thyroid morphogenesis. Knockdown of tshr function by morpholino microinjection into embryos did not affect early thyroid morphogenesis but caused defects in later functional differentiation. The thyroid phenotype observed in tshr morphants at later stages comprised a reduction in number and size of functional follicles, down-regulation of differentiation markers, as well as reduced thyroid transcription factor expression. A comparison of our results with phenotypes observed in mouse models of defective TSHR and cAMP signaling highlights the value of zebrafish as a model to enhance the understanding of functional differentiation in the vertebrate thyroid. (Molecular Endocrinology 25: 1579-1599, 2011)