View the Current Issue

Article

  • The EMBO Journal (2007) 26, 4445 - 4456
  • doi:10.1038/sj.emboj.7601883

Published online: 11 October 2007

Cited2, a coactivator of HNF4alpha, is essential for liver development

Xiaoling Qu1, Eric Lam1, Yong-Qiu Doughman2, Yu Chen1, Yu-Ting Chou1, Minh Lam3, Mona Turakhia1, Sally L Dunwoodie4, Michiko Watanabe2, Bing Xu1, Stephen A Duncan5 and Yu-Chung Yang1,3

  1. Department of Pharmacology and Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA
  2. Department of Pediatrics, Rainbow Babies and Children's Hospital, Case Western Reserve University School of Medicine, Cleveland, OH, USA
  3. Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA
  4. Developmental Biology Program, the Victor Chang Cardiac Research Institute, and Faculties of Science and Medicine, University of New South Wales, Sydney, Australia
  5. Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA

Correspondence to:

Yu-Chung Yang, Department of Pharmacology, Case Western Reserve University School of Medicine, 2109 Adelbert Road, W353, Cleveland, OH 44106-4965, USA. Tel.: +1 216 368 6931; Fax: +1 216 368 3395; E-mail: yxy36@cwru.edu

Received 27 April 2007; Accepted 18 September 2007

The transcriptional modulator Cited2 is induced by various biological stimuli including hypoxia, cytokines, growth factors, lipopolysaccharide (LPS) and flow shear. In this study, we report that Cited2 is required for mouse fetal liver development. Cited2-/- fetal liver displays hypoplasia with higher incidence of cell apoptosis, and exhibits disrupted cell-cell contact, disorganized sinusoidal architecture, as well as impaired lipid metabolism and hepatic gluconeogenesis. Furthermore, we demonstrated the physical and functional interaction of Cited2 with liver-enriched transcription factor HNF4alpha. Chromatin immunoprecipitation (ChIP) assays further confirmed the recruitment of Cited2 onto the HNF4alpha-responsive promoters and the reduced HNF4alpha binding to its target gene promoters in the absence of Cited2. Taken together, this study suggests that fetal liver defects in mice lacking Cited2 result, at least in part, from its defective coactivation function for HNF4alpha.

  • Keywords:

    • Cited2,
    • coactivator,
    • HNF4alpha,
    • liver development