Thyroid-specific enhancer-binding protein/NKX2.1 is required for the maintenance of ordered architecture and function of the differentiated thyroid
Thyroid-specific enhancer-binding protein/NKX2.1 is required for the maintenance of ordered architecture and function of the differentiated thyroid
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DOI：
10.1210/me.2005-0327
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发表时间：
2006-08-01
影响因子：
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通讯作者：
Kimura, Shioko
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文献类型：
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作者：
Kusakabe, Takashi;Kawaguchi, Akio;Kimura, Shioko
甲状腺特异性增强子结合蛋白（T/ebp）/Nkx2.1-null小鼠甲状腺在胚胎第12-13天通过细胞凋亡退化，而T/ebp/Nkx2.1-heterogyzgous小鼠表现出甲状腺功能减退，TSH水平升高。为了理解T/ebp/Nkx2.1在成人甲状腺中的作用，建立了甲状腺滤泡细胞特异性条件性敲除（KO）小鼠系T/ebp（fl/fl）; TPO-Cre，其在人甲状腺过氧化物酶（TPO）基因启动子下表达Cre重组酶。这些小鼠似乎是健康的，并表现出T/ebp/Nkx2.1表达的损失，在许多，但不是所有的，甲状腺滤泡细胞通过免疫组化和实时PCR确定，从而提出了T/ebp-甲状腺条件性低形态小鼠。对T/ebp（fl/fl）、T/ebp（fl/fl）; TPO-Cre和T/ebp（fl/ko）小鼠甲状腺的详细分析显示，T/ebp（fl/fl）; TPO-Cre小鼠可分为具有不同表型的两组：一个患有萎缩/退化的甲状腺滤泡，经常出现腺瘤和极高的血清TSH水平，而另一个具有改变的甲状腺结构，与通常在正常甲状腺中发现的那些相比，具有由过多数量的滤泡细胞组成的异常扩张的滤泡数量减少。后者的表型也观察到在老年T/ebp（fl/ko）小鼠甲状腺。使用来自T/ebp（fl/fl）、TPO-Cre、T/ebp（fl/ko）和T/ebp（fl/fl）小鼠的甲状腺以及用具有和不具有Cre表达的重组腺病毒处理的后者的体外三维甲状腺原代培养物证明，仅来自没有腺病毒Cre处理的T/ebp（fl/fl）小鼠的细胞形成滤泡结构。总之，这些结果表明，T/ebp/Nkx2.1是维持分化甲状腺正常结构和功能所必需的。
Thyroid-specific enhancer-binding protein (T/ebp)/Nkx2.1-null mouse thyroids degenerate by embryonic day (E) 12-13 through apoptosis whereas T/ebp/Nkx2.1-heterogyzgous mice exhibit hypothyroidism with elevated TSH levels. To understand the role of T/ebp/Nkx2.1 in the adult thyroid, a thyroid follicular cell-specific conditional knockout (KO) mouse line, T/ebp(fl/fl); TPO-Cre, was established that expresses Cre recombinase under the human thyroid peroxidase (TPO) gene promoter. These mice appeared to be healthy and exhibited loss of T/ebp/Nkx2.1 expression in many, but not all, thyroid follicular cells as determined by immunohistochemistry and real-time PCR, thus presenting a T/ebp-thyroid-conditional hypomorphic mice. Detailed analysis of the thyroids from T/ebp(fl/fl), T/ebp(fl/fl); TPO-Cre, and T/ebp(fl/ko) mice, where the latter mouse line is derived from crosses with the original T/ebp/Nkx2.1-heterozygous mice, revealed that T/ebp(fl/fl); TPO-Cre mice can be classified into two groups with different phenotypes: one having atrophic/degenerative thyroid follicles with frequent presence of adenomas and extremely high serum TSH levels, and the other having an altered thyroid structure with reduced numbers of extraordinary dilated follicles consisting of excessive numbers of follicular cells as compared with those usually found in the normal thyroid. The latter phenotype was also observed in aged T/ebp(fl/ko) mouse thyroids. In vitro three-dimensional thyroid primary cultures using thyroids from T/ebp(fl/fl); TPO-Cre, T/ebp(fl/ko), and T/ebp(fl/fl) mice, and the latter treated with recombinant adenovirus with and without Cre expression, demonstrated that only cells from T/ebp(fl/fl) mice without adeno-Cre treatment formed follicular structures. Taken together, these results suggest that T/ebp/Nkx2.1 is required for maintenance of the normal architecture and function of differentiated thyroids.