Cloning of Transcriptional Regulatory Factors for the Prolactin Gene Using a TRH Knockout Mice.

我们最近报道TRH缺陷小鼠表现出特征性的三级甲状腺功能减退。在本研究中，我们调查了这种三级甲状腺功能减退症是如何发生的，特别是在产前和产后阶段。免疫组化分析显示，一些TSH免疫阳性细胞的TRH-/-垂体胚胎17.5天和出生时。从TRH缺乏的母鼠出生的幼崽在出生时的突变垂体也没有表现出明显的形态学变化，表明没有要求无论是母亲或胚胎TRH的垂体促甲状腺激素细胞的发展。与此相反，明显减少的数量和染色的TSH阳性细胞的水平，观察出生后10天的突变垂体。在8周龄的突变垂体中也观察到类似的减少，而在其他垂体腺瘤产生细胞中没有观察到明显的变化，长时间的TRH给药完全逆转了这种作用。与这些形态学结果一致，TRH-/-小鼠在出生时表现出正常的甲状腺激素水平，但随后的出生后增加被抑制，导致甲状腺功能减退。正如预期的那样，在TRH-/-垂体TSH含量显着减少，只有40%的野生型。尽管突变小鼠出现甲状腺功能减退，但垂体TSH β和α mRNA水平均低于野生型垂体。这些表型变化是特定的垂体促甲状腺激素细胞。这些发现表明：1）TRH仅对出生后垂体促甲状腺激素细胞的正常功能的维持是必需的，包括甲状腺激素对TSH基因的正常反馈调节; 2）胎儿垂体促甲状腺激素细胞的正常发育不需要母体或胚胎TRH; 3）TRH缺陷的小鼠在出生时不表现出甲状腺功能减退。此外，TRH对垂体促甲状腺激素细胞的作用比对其他垂体促甲状腺激素细胞的作用更重要。

We recently reported that TRH-deficient mice showed characteristic tertiary hypothyroidism. In the present study, we investigated how this tertiary hypothyroidism occurred particularly in pre- and postnatal stages. Immunohistochemical analysis revealed that a number of TSH-immunopositive cells in the TRH-/- pituitary on embryonic day 17.5 and at birth. The mutant pituitary at birth in pups born from TRH-deficient dams also showed no apparent morphological changes, indicating no requirement of either maternal or embryonic TRH for the development of pituitary thyrotrophs. In contrast, apparent decrease in number and level of staining of TSH-positive cells were observed after postnatal day 10 in mutant pituitary. Similar decreases were observed in the 8-week-old mutant pituitary, while no apparent changes were observed in other pituitary hormone-producing cells, and prolonged TRH administration completely reversed this effect. Consistent with these morphological results, TRH-/- mice showed normal thyroid hormone levels at birth, but the subsequent postnatal increase was depressed, resulting in hypothyroidism. As expected, TSH content in the TRH-/- pituitary showed a marked reduction to only 40% of that in the wild-type. Despite hypothyroidism in the mutant mice, both the pituitary TSH β and alpha mRNA levels were lower than those of the wild-type pituitary. These phenotypic changes were specific to the pituitary of thyrotrophs. These findings indicated that 1) TRH is essential only for the postnatal maintenance of the normal function of pituitary thyrotrophs, including the normal feedback regulation of the TSH gene by thyroid hormone ; 2) neither maternal nor embryonic TRH is required for normal development of the fetal pituitary thyrotrophs ; and 3) TRH-deficient mice do not exhibit hypothyroidism at birth. Moreover, reflecting its name, TRH has more critical effects on the pituitary thyrotrophs than on other pituitary hormone-producing cells.