Abstract
The protein EP300 and its paralog CREBBP (CREB-binding protein) are ubiquitously expressed transcriptional co-activators and histone acetyl transferases1. The gene EP300 is essential for normal cardiac and neural development, whereas CREBBP is essential for neurulation, hematopoietic differentiation, angiogenesis and skeletal and cardiac development2,3,4,5. Mutations in CREBBP cause Rubinstein-Taybi syndrome, which is characterized by mental retardation, skeletal abnormalities and congenital cardiac defects6,7. The CBP/p300-interacting transactivator with ED-rich tail 2 (CITED2) binds EP300 and CREBBP with high affinity8 and regulates gene transcription8,9,10. 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 development11,12,13, we propose that abnormal embryogenesis in mice lacking Cited2 results, at least in part, from its role as a Tfap2 co-activator.
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Acknowledgements
We are grateful to R. Gardner and F. Brook for advice and to all those who generously gave us reagents. We thank R. Sumner, J. Corrigan, T. Swingler and C. Ibbitt for excellent technical help. J.J.E. and H.C.H. are supported by the Imperial Cancer Research Fund, J.N.M. by the Medical Research Council and H.F. and D.J.H. by the British Heart Foundation. These studies were funded by a Wellcome Senior Research Fellowship in Clinical Science award to S.B.
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Bamforth, S., Bragança, J., Eloranta, J. et al. Cardiac malformations, adrenal agenesis, neural crest defects and exencephaly in mice lacking Cited2, a new Tfap2 co-activator. Nat Genet 29, 469–474 (2001). https://doi.org/10.1038/ng768
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DOI: https://doi.org/10.1038/ng768
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