Cardiac malformations, adrenal agenesis, neural crest defects and exencephaly in mice lacking Cited2, a new Tfap2 co-activator
Cardiac malformations, adrenal agenesis, neural crest defects and exencephaly in mice lacking Cited2, a new Tfap2 co-activator
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DOI：
10.1038/ng768
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发表时间：
2001-12-01
期刊：
影响因子：
30.8
通讯作者：
Bhattacharya, S
中科院分区：
文献类型：
--
作者：
Bamforth, SD;Bragança, J;Bhattacharya, S
蛋白质EP 300和它的副产物CREBBP（CREB结合蛋白）是广泛表达的转录共激活因子和组蛋白乙酰基转移酶。基因EP 300对于正常心脏和神经发育是必需的，而CREBBP对于神经形成、造血分化、血管生成以及骨骼和心脏发育是必需的（2-5）。CREBBP突变导致Rubinstein-Taybi综合征，其特征为智力迟钝、骨骼异常和先天性心脏缺陷（6，7）。CBP/p300相互作用反式激活因子与富含ED的尾2（CITED 2）以高亲和力结合EP 300和CREBBP（8）并调节基因转录（8-10）。在这里，我们发现引用2（-/-）胚胎死亡心脏畸形，肾上腺发育不全，异常颅神经节和露脑。心脏缺损包括房间隔缺损、室间隔缺损、主动脉瓣重叠、右心室双出口、永存动脉干和右侧主动脉弓。我们发现中脑区域的细胞凋亡增加，并且在胚胎中期表达ErbB 3的神经嵴细胞显著减少。我们发现CITED 2与转录因子AP-2（TFAP 2）的所有亚型相互作用并共激活。TFAP 2亚型的反式激活在Cited 2（-/-）胚胎成纤维细胞中是有缺陷的，并被异位表达的CITED 2所拯救。由于某些Tfap 2同种型在神经嵴、神经管和心脏发育中是必需的（11-13），我们提出缺乏Cited 2的小鼠中的异常胚胎发生至少部分地是由于其作为Tfap 2共激活剂的作用。
The protein EP300 and its paralog CREBBP (CREB-binding protein) are ubiquitously expressed transcriptional co-activators and histone acetyl transferases'. The gene EP300 is essential for normal cardiac and neural development, whereas CREBBP is essential for neurulation, hematopoietic differentiation, angiogenesis and skeletal and cardiac development(2-5). Mutations in CREBBP cause Rubinstein-Taybi syndrome, which is characterized by mental retardation, skeletal abnormalities and congenital cardiac defects(6,7). The CBP/p300-interacting transactivator with ED-rich tail 2 (CITED2) binds EP300 and CREBBP with high affinity(8) and regulates gene transcription(8-10). Here we show that Cited2(-/-) embryos die with cardiac malformations, adrenal agenesis, abnormal cranial ganglia and exencephaly. The cardiac defects include atrial and ventricular septal defects, overriding aorta, double-outlet right ventricle, persistent truncus arteriosus and right-sided aortic arches. We find increased apoptosis in the midbrain region and a marked reduction in ErbB3-expressing neural crest cells in mid-embryogenesis. We show that CITED2 interacts with and co-activates all isoforms of transcription factor AP-2 (TFAP2). Transactivation by TFAP2 isoforms is defective in Cited2(-/-) embryonic fibroblasts and is rescued by ectopically expressed CITED2. As certain Tfap2 isoforms are essential in neural crest, neural tube and cardiac development(11-13), we propose that abnormal embryogenesis in mice lacking Cited2 results, at least in part, from its role as a Tfap2 co-activator.