Müller Kathrin, Führer Dagmar, Mittag Jens, Klöting Nora, Blüher Matthias, Weiss Roy E, Many Marie-Christine, Schmid Kurt Werner, Krohn Knut
Department of Internal Medicine, University of Leipzig, Germany.
Mol Endocrinol. 2011 Nov;25(11):1867-79. doi: 10.1210/me.2011-0065. Epub 2011 Oct 6.
Although TSH stimulates all aspects of thyroid physiology IGF-I signaling through a tyrosine kinase-containing transmembrane receptor exhibits a permissive impact on TSH action. To better understand the importance of the IGF-I receptor in the thyroid in vivo, we inactivated the Igf1r with a Tg promoter-driven Cre-lox system in mice. We studied male and female mice with thyroidal wild-type, Igf1r(+/-), and Igf1r(-/-) genotypes. Targeted Igf1r inactivation did transiently reduce thyroid hormone levels and significantly increased TSH levels in both heterozygous and homozygous mice without affecting thyroid weight. Histological analysis of thyroid tissue with Igf1r inactivation revealed hyperplasia and heterogeneous follicle structure. From 4 months of age, we detected papillary thyroid architecture in heterozygous and homozygous mice. We also noted increased body weight of male mice with a homozygous thyroidal null mutation in the Igf1r locus, compared with wild-type mice, respectively. A decrease of mRNA and protein for thyroid peroxidase and increased mRNA and protein for IGF-II receptor but no significant mRNA changes for the insulin receptor, the TSH receptor, and the sodium-iodide-symporter in both Igf1r(+/-) and Igf1r(-/-) mice were detected. Our results suggest that the strong increase of TSH benefits papillary thyroid hyperplasia and completely compensates the loss of IGF-I receptor signaling at the level of thyroid hormones without significant increase in thyroid weight. This could indicate that the IGF-I receptor signaling is less essential for thyroid hormone synthesis but maintains homeostasis and normal thyroid morphogenesis.
尽管促甲状腺激素（TSH）刺激甲状腺生理的各个方面，但通过含酪氨酸激酶的跨膜受体的胰岛素样生长因子-I（IGF-I）信号传导对TSH的作用具有允许性影响。为了更好地理解IGF-I受体在体内甲状腺中的重要性，我们在小鼠中使用Tg启动子驱动的Cre-lox系统使Igf1r失活。我们研究了具有甲状腺野生型、Igf1r(+/-)和Igf1r(-/-)基因型的雄性和雌性小鼠。靶向Igf1r失活在杂合子和纯合子小鼠中均短暂降低了甲状腺激素水平并显著提高了TSH水平，而不影响甲状腺重量。对Igf1r失活的甲状腺组织进行组织学分析发现增生和卵泡结构异质性。从4个月大开始，我们在杂合子和纯合子小鼠中检测到甲状腺乳头状结构。我们还注意到，与野生型小鼠相比，Igf1r基因座纯合甲状腺无效突变的雄性小鼠体重增加。在Igf1r(+/-)和Igf1r(-/-)小鼠中均检测到甲状腺过氧化物酶的mRNA和蛋白减少，IGF-II受体的mRNA和蛋白增加，但胰岛素受体、TSH受体和钠碘同向转运体的mRNA无显著变化。我们的结果表明，TSH的强烈增加有利于甲状腺乳头状增生，并在甲状腺激素水平上完全补偿了IGF-I受体信号的丧失，而甲状腺重量没有显著增加。这可能表明IGF-I受体信号传导对甲状腺激素合成不太重要，但维持体内平衡和正常甲状腺形态发生。
