|Budget Amount *help
¥12,800,000 (Direct Cost: ¥12,800,000)
Fiscal Year 1999: ¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 1998: ¥7,800,000 (Direct Cost: ¥7,800,000)
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.