HUMAN FETAL PALATAL CORTICOID RECEPTORS AND TERATOGENS FOR CLEFT-PALATE
HUMAN FETAL PALATAL CORTICOID RECEPTORS AND TERATOGENS FOR CLEFT-PALATE
复制标题
DOI：
10.1038/272464a0
复制
发表时间：
1978-01-01
期刊：
影响因子：
64.8
通讯作者：
KATSUMATA, M
中科院分区：
文献类型：
--
作者：
GOLDMAN, AS;SHAPIRO, BH;KATSUMATA, M
通过对妊娠动物给予糖皮质激素，可以在各种哺乳动物物种中实验诱导CLEFT继发性腭1 -4。众所周知，近交系小鼠对可的松诱导腭裂的易感性差异已被解释为胎儿面部间质糖皮质激素受体水平的遗传差异5，6。特别是一种蛋白质的量，其等电点（pI）约为7.0，似乎与各种菌株对可的松诱导的腭裂的易感性密切相关6。研究还表明，C57 BL/10（B10）和A/J小鼠之间腭裂易感性的大部分差异可以通过H-2连锁基因7，8来解释，并且从胎儿腭组织的细胞质组分中获得的皮质醇结合蛋白水平存在H-2连锁变异6。由于皮质激素在靶组织中形成特异性细胞质皮质醇受体复合物，其与基因组相互作用，导致转录的激活或抑制9，10，在H-2位点或其附近的基因产物似乎是糖皮质激素受体，其水平必须升高才能发生腭裂。作为第一步，以确定这种机制是否可以在人类中运作，我们已经研究了是否人腭间充质细胞，培养后不久，从胎儿的关键时期的第二腭关闭，含有糖皮质激素受体。我们在这里表明，这些细胞具有特异性的糖皮质激素受体蛋白与地塞米松和曲安奈德的高亲和力，地塞米松是取代其结合位点，只有药物产生腭裂敏感的小鼠品系。因此，人胎儿在腭器官发生的关键期后立即含有活跃的糖皮质激素受体机制，这可能与腭裂有关。
CLEFT secondary palate can be induced experimentally in various mammalian species by the administration of glucocorticoids to pregnant animals1–4. The well known differences in susceptibility to cortisone-induced cleft palate in inbred strains of mice have been explained in terms of genetic differences in foetal facial mesenchymal glucocorticoid receptor levels5,6. The quantity of one protein in particular, with an isoelectric point (pI) of approximately 7.0, seems to be correlated rather closely with the susceptibility of various strains to cortisone-induced cleft palate6. It has also been shown that much of the difference in cleft palate susceptibility between C57BL/10 (B10) and A/J mice can be accounted for byH–2-linked genes7,8, and that there isH–2-linked variation in the level of cortisol-binding proteins obtained from the cytosol fraction of foetal palatal tissue6. As corticoids form a specific cytoplasmic cortisol receptor complex in target tissues which interacts with the genome resulting in activation or depression of transcription9,10, a product of a gene in or near theH–2locus seems to be the glucocorticoid receptor, the level of which has to be raised for cleft palate to occur. As a first step to determine whether such a mechanism may operate in humans, we have examined whether human palatal mesenchymal cells, obtained in cultures from foetuses shortly after the critical period of secondary palatal closure, contain glucocorticoid receptors. We show here that these cells have specific glucocorticoid receptor proteins with high affinity for dexamethasone and triamcinolone acetonide, and that dexamethasone is displaced from its binding sites only by drugs which produce cleft palate in sensitive mouse strains. Thus, the human foetus contains an active glucocorticoid receptor mechanism immediately after the critical period of palatal organogenesis, which may be involved in palatal clefting.