Role of the NF-ATc transcription factor in morphogenesis of cardiac valves and septum
Role of the NF-ATc transcription factor in morphogenesis of cardiac valves and septum
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作者：
de la Pompa, JL;Timmerman, LA;Mak, TW
在淋巴细胞中，早期免疫应答基因的表达受NF-AT转录因子（1，2）调节，这些转录因子在通过Ca 2+依赖性磷酸酶钙调神经磷酸酶（3）去磷酸化后转移至细胞核。我们在这里报告说，小鼠轴承中断在NF-ATc基因不能开发正常的心脏瓣膜和隔膜和循环衰竭前14.5天的发展。NF-ATc在第7.5天首先在心脏中表达，并且限于内皮细胞，一种产生瓣膜和隔膜的特化内皮细胞。在内皮细胞内，特定的诱导事件似乎激活了NF-ATc：它仅定位于与心脏胶质和心肌交界面相邻的内皮细胞中的细胞核，这被认为是对瓣膜原基的诱导刺激（4）。用FK 506（一种特异性钙调磷酸酶抑制剂）处理野生型胚胎（5），可阻止NF-ATc的核定位。这些数据表明，Ca 2 +/钙调神经磷酸酶/NF-ATc信号通路是必不可少的正常心脏瓣膜和隔膜的形态发生，因此，NF-ATc及其调节途径是潜在的先天性人类心脏病的遗传缺陷的候选人。
In lymphocytes, the expression of early immune response genes is regulated by NF-AT transcription factors(1,2) which translocate to the nucleus after dephosphorylation by the Ca2+-dependent phosphatase, calcineurin(3). We report here that mice bearing a disruption in the NF-ATc gene fail to develop normal cardiac valves and septa and die of circulatory failure before day 14.5 of development. NF-ATc is first expressed in the heart at day 7.5, and is restricted to the endocardium, a specialized endothelium that gives rise to the valves and septum. Within the endocardium, specific inductive events appear to activate NF-ATc: it is localized to the nucleus only in endocardial cells that are adjacent to the interface with the cardiac jelly and myocardium, which are thought to give the inductive stimulus to the valve primordia(4). Treatment of wild-type embryos with FK506, a specific calcineurin inhibitor(5), prevents nuclear localization of NF-ATc. These data indicate that the Ca2+/calcineurin/NF-ATc signalling pathway is essential for normal cardiac valve and septum morphogenesis; hence, NF-ATc and its regulatory pathways are candidates for genetic defects underlying congenital human heart disease.