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The role of thyroid hormone action in the developing brain and the mechanism generating critical period of its action.

甲状腺激素在大脑发育中的作用及其作用关键期的产生机制。

基本信息

批准号：
14370020
负责人：
KOIBUCHI Noriyuki
金额：
$ 8.83万
依托单位：
Gunma University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370020/
关键词：
Thyroid hormone Cerebellum Development Critical Period Gene expression Transcriptional cofactor Endocrine disrupters

项目摘要

The aim of this study was to investigate the effect of thyroid hormone(TH) on brain development and the mechanisms generating the critical period of its action, using a rodent cerebellum as a model system.Although the expression of TH receptor(TR) is greater in adult cerebellum, the sensitivity to TH is much less compared to that during cerebellar development. Thus, unknown factor other than TR may regulate its sensitivity. Thus, we investigated the ontogenic changes in the expression of SRC-1 that is a coactivator of TR to regulate transcription, by immunohistochemistry in the developing rat brain. SRC-1 was strongly expressed in the Purkinje cell. It was also weakly expressed in the internal granule cells. By Western blot, the level of SRC-1 protein was greatest at postnatal day (P) 14, the period when TH sensitivity is greatest.Simultaneously, we have tried to clone the novel TR-binding protein in the fetal cerebellum, using Ras-Sos yeast two hybrid screening. We have identified a protein that has been known as OVCOV-1. The size of this protein is 365 amino acid in length. By sequence analysis, we found that three LXXLL motiefs that are responsible for binding to nuclear receptors.Since previous studies have shown that perinatal exposure to several environmental chemical may induce abnormal brain development similar to those seen in hypothyroidism, we have examined the effect of polychlorinated biphenyls on TR-mediated transcription. Low dose (100 pM) PCB suppressed TR-mediated transcription. The effect of PCB was exerted by partial dissociation of TR from TH-responsive element of DNA.

本研究以啮齿类动物小脑为模型系统，探讨甲状腺激素（TH）对脑发育的影响及其作用关键期产生的机制。因此，TR以外的未知因素可能调节其敏感性。因此，我们研究了SRC-1的表达，这是一个TR的共激活因子，以调节转录的个体发生的变化，在发育中的大鼠大脑的免疫组织化学。SRC-1在浦肯野细胞中强表达。它也在内部颗粒细胞中弱表达。Western blot结果显示，SRC-1蛋白在出生后第14天（P 14）表达最高，这一时期是TH敏感性最高的时期。我们已经鉴定出一种被称为OVCOV-1的蛋白质。该蛋白质的长度为365个氨基酸。通过序列分析，我们发现了三个负责与核受体结合的LXXLL基序，由于以前的研究表明，围产期暴露于几种环境化学物质可能会导致异常的脑发育类似于甲状腺功能减退症，我们已经检查了多氯联苯对TR介导的转录的影响。低剂量（100 pM）PCB抑制TR介导的转录。PCB的作用是通过TR与DNA TH反应元件的部分解离来实现的。