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

我们最近报道了trh缺乏小鼠表现出特征性的三期甲状腺功能减退。在目前的研究中，我们调查了这种三期甲状腺功能减退是如何发生的，特别是在产前和产后阶段。免疫组化分析显示，在胚胎17.5天和出生时，TRH-/-垂体中有大量tsh免疫阳性细胞。TRH缺陷母鼠所生幼鼠出生时的垂体突变体也未表现出明显的形态学变化，表明垂体促甲状腺症的发育不需要母体或胚胎的TRH。与此相反，出生后第10天突变垂体tsh阳性细胞的数量和染色水平明显下降。在8周大的突变垂体中也观察到类似的下降，而在其他垂体激素产生细胞中没有观察到明显的变化，延长TRH治疗完全逆转了这种作用。与这些形态学结果一致，TRH-/-小鼠在出生时甲状腺激素水平正常，但随后的出生后增加受到抑制，导致甲状腺功能减退。正如预期的那样，TRH-/-垂体中的TSH含量显著降低，仅为野生型的40%。尽管突变小鼠有甲状腺功能减退，但其垂体TSH β和α mRNA水平均低于野生型垂体。这些表型变化是甲状腺功能亢进患者的垂体所特有的。这些结果表明：1)TRH仅对产后维持垂体促甲状腺机能的正常功能起重要作用，包括甲状腺激素对TSH基因的正常反馈调节；2)胎儿垂体甲状腺功能亢进症的正常发育既不需要母体TRH，也不需要胚胎TRH；3) trh缺陷小鼠在出生时不表现出甲状腺功能减退。此外，正如其名，TRH对垂体促甲状腺细胞的作用比对其他垂体激素产生细胞的作用更为关键。

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.