Embryonic exposure to excess thyroid hormone causes thyrotrope cell death.
Embryonic exposure to excess thyroid hormone causes thyrotrope cell death.
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DOI：
10.1172/jci70038
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发表时间：
2014-01
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影响因子：
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通讯作者：
Ksenia N. Tonyushkina;Meng‐Chieh Shen;Theresa M Ortiz-Toro;R. Karlstrom
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作者：
Ksenia N. Tonyushkina;Meng‐Chieh Shen;Theresa M Ortiz-Toro;R. Karlstrom
中枢性先天性甲状腺功能减退症(CCH)在妊娠期甲亢妇女所生的孩子中更为常见，提示甲状腺激素(TH)在中枢甲状腺调节中的作用。以斑马鱼胚胎作为甲状腺轴发育的模型，研究了促甲状腺功能负反馈调节的个体发育，并探讨了过量TH对促甲状腺激素发育的影响。我们发现，在受精后48h，促甲状腺激素β亚单位(Tshb)和2型脱碘酶(DiO2)在斑马鱼甲状腺中共表达，在受精后96h，TH驱动的Tshb转录负反馈调节出现在甲状腺轴上。负反馈调节与发育中的甲状腺滤泡的全身性TH水平升高有关。我们使用了一条在tshb启动子控制下表达绿色荧光蛋白的转基因斑马鱼，在体内跟踪促甲状腺激素的命运。延时成像显示，早期暴露于升高的TH会导致甲状腺细胞死亡。在去除多余的TH后，促甲状腺激素数量缓慢恢复。这些数据表明，在脑垂体发育的关键时期，短暂的TH暴露会对促甲状腺激素的数量产生深远的影响，并可能对促甲状腺激素(TSH)产生的功能储备和以后生命中TSH的设定点产生长期影响。
Central congenital hypothyroidism (CCH) is more prevalent in children born to women with hyperthyroidism during pregnancy, suggesting a role for thyroid hormone (TH) in the development of central thyroid regulation. Using the zebrafish embryo as a model for thyroid axis development, we have characterized the ontogeny of negative feedback regulation of thyrotrope function and examined the effect of excess TH on thyrotrope development. We found that thyroid-stimulating hormone β subunit (tshb) and type 2 deiodinase (dio2) are coexpressed in zebrafish thyrotropes by 48 hours after fertilization and that TH-driven negative feedback regulation of tshb transcription appears in the thyroid axis by 96 hours after fertilization. Negative feedback regulation correlated with increased systemic TH levels from the developing thyroid follicles. We used a transgenic zebrafish that expresses GFP under the control of the tshb promoter to follow thyrotrope fates in vivo. Time-lapse imaging revealed that early exposure to elevated TH leads to thyrotrope cell death. Thyrotrope numbers slowly recovered following the removal of excess TH. These data demonstrate that transient TH exposure profoundly impacts the thyrotrope population during a critical period of pituitary development and may have long-term implications for the functional reserve of thyroid-stimulating hormone (TSH) production and the TSH set point later in life.