Wallace H, Pate A, Bishop J O
Centre for Genome Research, University of Edinburgh, UK.
J Endocrinol. 1995 May;145(2):251-62. doi: 10.1677/joe.0.1450251.
Experiments were designed to distinguish between neonatal effects due to maternal thyroxine (T4) deprivation and those due to autonomous (fetus/pup) T4 deprivation, employing mice heterozygous for the bTG-tk transgene TG66,19 which specifically directs high-level expression of herpes virus type I thymidine kinase to the thyrocytes. Heterozygous TG66.19 females were either untreated or Ganciclovir was administered to destroy their thyrocytes and so render them T4-deficient. When mated to normal males these heterozygous females are expected to produce on average 50% normal and 50% heterozygous transgenic conceptuses. Ganciclovir was administered to the dams (both untreated and Ganciclovir-pretreated) during days 14-18 of gestation. At optimum levels of in utero Ganciclovir administration the non-transgenic pups showed no discernible effect while the transgenic pups were rendered athyrocytic and completely T4-deficient. The dams pretreated with Ganciclovir are hypothyroid throughout gestation, while the dams to which Ganciclovir was administered for the first time during gestation are not expected to become hypothyroid until about the time of parturition. In this way four sets of pups were generated for purposes of comparison: hypothyroid (transgenic) and euthyroid (non-transgenic) pups born to euthyroid dams and hypothyroid and euthyroid pups born to hypothyroid (Ganciclovir-pretreated) dams. Normal growth during days 1-10 after birth was dominated by the T4 status of the dam during gestation. Growth during days 11-21 and the correct timing of eye opening and ear elevation were dominated by the autonomous T4 status of the fetus/pup. The timely development of the surface-righting reflex (relative to weight gain) was shown to require both maternal and fetus/pup T4. The development of the cliff-avoidance reflex was independent of the T4 status of both pup and dam and of pup weight. The size of the pups at birth depended primarily on a normal T4 status in the dam but surprisingly T4 deficiency in fetuses/pups partly compensated for maternal T4 deficiency. The results presented here clearly demonstrate the utility of the HSV-tk-transgene-Ganciclovir-administration protocol in studying the interplay of maternal and fetal T4 deprivation in rodents.
实验旨在区分母体甲状腺素（T4）缺乏所致的新生儿效应与自主（胎儿/幼崽）T4缺乏所致的效应，实验采用了bTG-tk转基因TG66,19的杂合小鼠，该转基因可特异性地将I型疱疹病毒胸苷激酶的高水平表达导向甲状腺细胞。杂合的TG66.19雌性小鼠要么不接受治疗，要么给予更昔洛韦以破坏其甲状腺细胞，从而使其T4缺乏。当与正常雄性小鼠交配时，这些杂合雌性小鼠预计平均会产生50%的正常和50%的杂合转基因胚胎。在妊娠第14至18天期间，给母鼠（未治疗的和经更昔洛韦预处理的）注射更昔洛韦。在子宫内给予最佳水平的更昔洛韦时，非转基因幼崽未表现出明显影响，而转基因幼崽则变为无甲状腺细胞且完全T4缺乏。经更昔洛韦预处理的母鼠在整个妊娠期甲状腺功能减退，而在妊娠期首次给予更昔洛韦的母鼠预计直到分娩时才会出现甲状腺功能减退。通过这种方式，产生了四组幼崽用于比较：甲状腺功能正常的母鼠所生的甲状腺功能减退（转基因）和甲状腺功能正常（非转基因）的幼崽，以及甲状腺功能减退（经更昔洛韦预处理）的母鼠所生的甲状腺功能减退和甲状腺功能正常的幼崽。出生后1至10天的正常生长主要受母鼠妊娠期T4状态的影响。11至21天的生长以及睁眼和耳部竖起的正确时间主要受胎儿/幼崽自主T4状态的影响。表面翻正反射的及时发育（相对于体重增加）显示需要母体和胎儿/幼崽的T4。悬崖回避反射的发育与幼崽和母鼠的T4状态以及幼崽体重无关。幼崽出生时的大小主要取决于母鼠正常的T4状态，但令人惊讶的是，胎儿/幼崽的T4缺乏部分补偿了母体T4缺乏。此处呈现的结果清楚地证明了HSV-tk转基因-更昔洛韦给药方案在研究啮齿动物母体和胎儿T4缺乏相互作用方面的效用。
