The Cited2 knockout mouse phenotype indicates that Cited2, a recently discovered transcriptional activator, is critical for morphogenesis of the conotruncus (cardiac outflow tract) and the cranial neural tube. Both of these tissues are known to be hypoxic during their development. Cited2 has been shown in in vitro systems to effectively compete with hypoxia-inducible factor 1-alpha (HIF-1alpha) for binding to the CH1 domain of CBP/p300 and to negatively regulate hypoxia-responsive gene expression. Up regulation of hypoxia inducible genes in the Cited2-/- embryo supports this hypothesis. Thus, Cited2 may be especially required for modulating the hypoxia response in those embryonic tissues that experience the lowest oxygen tension during normal development. We will test this hypothesis in mouse and chicken embryos with our main focus on the cardiac outflow tract (OFT).
Aim 1 : Determine in which cell type or cell types Cited2 expression is required for normal development. We will first determine in detail the expression of the Cited2 protein and mRNA in the embryo at critical stages in heart and neural tube morphogenesis and compare to hypoxic and apoptotic sites. We will specifically knock out Cited2 in the neural crest cells or cardiomyocytes using the Cre-lox system and assay the consequences.
Aim 2 : Test using in vivo systems the hypothesis that Cited2 is required to compete with HIF-Ia for CBP/p300 binding to down-regulate the hypoxia response in the heart. We will reduce Cited2 action specifically in the cardiomyocytes of the avian OFT and observe the consequences to morphogenesis and the hypoxia response including coronary vascular development. We will cross the Cited2 mice with HIF-Ia mice to determine whether the HIF-Ia gene dosage can modulate Cited2 action and vice versa. These studies will not only provide information critical to our understanding of normal and abnormal heart and neural development but also elucidate the complex interplay between transcription factors and co-factors in vivo.
| Yang, Ke; Doughman, Yong-Qiu; Karunamuni, Ganga et al. (2009) Expression of active Notch1 in avian coronary development. Dev Dyn 238:162-70 |
| Chen, Yu; Carlson, Eric C; Chen, Zhi-Yi et al. (2009) Conditional deletion of Cited2 results in defective corneal epithelial morphogenesis and maintenance. Dev Biol 334:243-52 |
| Wikenheiser, Jamie; Wolfram, Julie A; Gargesha, Madhusudhana et al. (2009) Altered hypoxia-inducible factor-1 alpha expression levels correlate with coronary vessel anomalies. Dev Dyn 238:2688-700 |
| Xu, Bing; Qu, Xiaoling; Gu, Shi et al. (2008) Cited2 is required for fetal lung maturation. Dev Biol 317:95-105 |
| Chen, Yu; Doughman, Yong-qiu; Gu, Shi et al. (2008) Cited2 is required for the proper formation of the hyaloid vasculature and for lens morphogenesis. Development 135:2939-48 |
| Qu, Xiaoling; Lam, Eric; Doughman, Yong-Qiu et al. (2007) Cited2, a coactivator of HNF4alpha, is essential for liver development. EMBO J 26:4445-56 |
| Chen, Yu; Haviernik, Peter; Bunting, Kevin D et al. (2007) Cited2 is required for normal hematopoiesis in the murine fetal liver. Blood 110:2889-98 |
| Xu, Bing; Doughman, Yongqiu; Turakhia, Mona et al. (2007) Partial rescue of defects in Cited2-deficient embryos by HIF-1alpha heterozygosity. Dev Biol 301:130-40 |
| Wikenheiser, Jamie; Doughman, Yong-Qiu; Fisher, Steven A et al. (2006) Differential levels of tissue hypoxia in the developing chicken heart. Dev Dyn 235:115-23 |
| Barbosky, Laura; Lawrence, David K; Karunamuni, Ganga et al. (2006) Apoptosis in the developing mouse heart. Dev Dyn 235:2592-602 |
