Farwell Alan P, Dubord-Tomasetti Susan A, Pietrzykowski Andrzej Z, Leonard Jack L
University of Massachusetts Medical School, Worcester, 01655, USA.
Endocrinology. 2006 May;147(5):2567-74. doi: 10.1210/en.2005-1272. Epub 2006 Feb 9.
Two well-characterized nongenomic actions of thyroid hormone in cultured brain tissues are: 1) regulation of type 2 iodothyronine 5'deiodinase (D2) activity and 2) regulation of actin polymerization. In particular, the latter is likely to have profound effects on neuronal migration in the developing brain. In this study, we determined whether these nongenomic actions also occurred in vivo during brain development. Neonatal hypothyroidism was induced by propylthiouracil given to pregnant dams beginning on d17 of gestation and continued throughout the neonatal period. On postnatal d 14, rats were injected with either cold or [(125)I]-labeled iodothyronines and killed sequentially after injection. In contrast to reports in the adult rat, all three iodothyronines readily and equally entered developing brain tissues. As expected, cerebrocortical D2 activity was markedly elevated in the hypothyroid brain and both reverse T(3) (rT(3)) and T(4) rapidly decreased D2 to euthyroid levels within 3 h. Furthermore, cerebellar G-actin content in the hypothyroid rat was approximately 5-fold higher than in the euthyroid rat. Again, both rT(3) and T(4) rapidly decreased the G-actin content by approximately 50%, with a reciprocal increase in F-actin content to euthyroid levels without altering total actin. Neither T(3) nor vehicle had any effect on D2 activity in the cortex or G- or F-actin content in the cerebellum. The thyroid hormone-dependent regulation of actin polymerization in the rat brain provides a mechanism by which this morphogenic hormone can influence neuronal migration independent of the need for altered gene transcription. Furthermore, these data suggest a prominent role for rT(3) during brain development.
1）对2型碘甲状腺原氨酸5'-脱碘酶（D2）活性的调节，以及2）对肌动蛋白聚合的调节。特别是，后者可能对发育中的大脑中的神经元迁移产生深远影响。在本研究中，我们确定了这些非基因组作用在大脑发育过程中是否也在体内发生。通过在妊娠第17天开始给怀孕的母鼠注射丙硫氧嘧啶来诱导新生儿甲状腺功能减退，并在整个新生儿期持续给药。在出生后第14天，给大鼠注射冷的或[（125）I]标记的甲状腺激素，并在注射后依次处死。与成年大鼠的报道相反，所有三种甲状腺激素都能轻松且同等程度地进入发育中的脑组织。正如预期的那样，甲状腺功能减退的大脑中脑皮质D2活性明显升高，而反式T3（rT3）和T4在3小时内迅速将D2活性降至甲状腺功能正常水平。此外，甲状腺功能减退大鼠的小脑G-肌动蛋白含量比甲状腺功能正常的大鼠高约5倍。同样，rT3和T4都迅速将G-肌动蛋白含量降低了约50%，同时F-肌动蛋白含量相应增加至甲状腺功能正常水平，而总肌动蛋白含量不变。T3或溶剂对照对皮质中的D2活性或小脑中的G-或F-肌动蛋白含量均无任何影响。大鼠脑中甲状腺激素依赖性的肌动蛋白聚合调节提供了一种机制，通过该机制这种形态发生激素可以独立于基因转录改变的需求来影响神经元迁移。此外，这些数据表明rT3在大脑发育过程中起着重要作用。
