Cardiac malformations, adrenal agenesis, neural crest defects and exencephaly in mice lacking Cited2, a new Tfap2 co-activator

Abstract

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. Mutations in CREBBP cause Rubinstein-Taybi syndrome, which is characterized by mental retardation, skeletal abnormalities and congenital cardiac defects. The CBP/p300-interacting transactivator with ED-rich tail 2 (CITED2) binds EP300 and CREBBP with high affinity and regulates gene transcription. 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, we propose that abnormal embryogenesis in mice lacking Cited2 results, at least in part, from its role as a Tfap2 co-activator.

Proper expression of the Gcn5 histone acetyltransferase is required for neural tube closure in mouse embryos

“…The normal expression of both Twist and Cart1 in the Gcn5 mutants indicates head mesenchyme forms normally in these mutants. Cranial NTDs have also been reported in Cited2, p300, and CBP mutant embryos (Yao et al, 1998;Oike et al, 1999;Bamforth et al, 2001;Greene and Copp, 2005). Quantitative PCR analyses indicate that Gcn5 is not required for expression of these genes (Fig.…”

Profiling and functional annotation of mRNA gene expression in pediatric rhabdomyosarcoma and Ewing's sarcoma

“…CITED2 forms a binary complex with CEBPB that is required to enhance transcriptional activation at numerous promoters. 41,42 For example, gene knockout studies 43 indicate that both CITED2 and CEBPB function as coactivators for the transcription factor AP2. A functional CIT-ED2/CEBPB complex is required for prenatal development, in particular for formation of the neural crest and heart formation.…”

Cited2 modulates TGF-β-mediated upregulation of MMP9

“…Elevated level of Cited2 then functions to downregulate hypoxia inducible factor (HIF)-1-driven transcription by competing with HIF-1a for binding to CBP/p300 Yin et al, 2002;Freedman et al, 2003). We and others have shown that disruption of the gene encoding Cited2 is embryonic lethal and causes defects in the development of heart and neural tube (Bamforth et al, 2001;Barbera et al, 2002;Yin et al, 2002).…”