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Blood, 15 October 2007, Vol. 110, No. 8, pp. 2889-2898. Prepublished online as a Blood First Edition Paper on July 20, 2007; DOI 10.1182/blood-2007-01-066316.
Submitted January 4, 2007
Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH * Corresponding author; email: yu-chung.yang{at}case.edu.
Cited2 [cAMP-responsive element-binding protein (CBP)/p300-interacting transactivators with glutamic acid (E) and aspartic acid (D)-rich tail 2] is a newly identified transcriptional modulator. Knockout of the Cited2 gene results in embryonic lethality with embryos manifesting heart and neural tube defects. Cited2-/- fetal liver displayed significant reduction in the numbers of Lin-c-Kit+Sca-1+ cells, Lin-c-Kit+ cells and progenitor cells of different lineages. Fetal liver cells from Cited2-/- embryos gave rise to markedly reduced number of colonies in the colony-forming unit assay. Primary and secondary transplantation studies showed significantly compromised reconstitution of T lymphoid, B lymphoid and myeloid lineages in mice transplanted with Cited2-/- fetal liver cells. Competitive reconstitution experiments further showed that fetal liver HSC function is severely impaired due to Cited2 deficiency. Microarray analysis showed decreased expression of Wnt5a and a panel of myeloid molecular markers such as PRTN3, MPO, neutrophil elastase, Cathepsin G and eosinophil peroxidase in Cited2-/- fetal livers. Decreased expression of Bmi-1, Notch1, LEF-1, Mcl-1 and GATA2 was also observed in Cited2-/- lin-c-Kit+ cells. The present study uncovers for the first time a novel role of Cited2 in the maintenance of hematopoietic homeostasis during embryogenesis and thus provides new insights into the molecular regulation of hematopoietic development.
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