Cited2 is required for normal hematopoiesis in the murine fetal liver
Cited2 is required for normal hematopoiesis in the murine fetal liver
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DOI：
10.1182/blood-2007-01-066316
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发表时间：
2007-10-15
期刊：
影响因子：
20.3
通讯作者：
Yang, Yu-Chung
中科院分区：
文献类型：
--
作者：
Chen, Yu;Haviernik, Peter;Yang, Yu-Chung
Cited 2（cAMP-responsive element-binding protein [CBP]/p300-interactactyltransactivators; with glutamic acid [E] and aspartic acid [D]-rich tail 2）是一种新发现的转录调节因子。Cited 2基因的敲除导致胚胎死亡，胚胎表现出心脏和神经管缺陷。引用的2（-/-）胎肝显示Lin（-）cKit（+）Sca-1（+）细胞、Lin（-）c-Kit（+）细胞和不同谱系的祖细胞的数量显著减少。来自Cited 2（-/-）胚胎的胎肝细胞在集落形成单位测定中引起集落数量显著减少。初次和二次移植研究显示，接受Cited 2（-/-）胎肝细胞移植的小鼠中T淋巴、B淋巴和骨髓谱系的重建显著受损。竞争性重建实验进一步表明，胎肝造血干细胞（HSC）功能严重受损，由于Cited 2缺陷。微阵列分析显示，在Cited 2（-/-）胎肝中，Wnt 5a和一组髓系分子标记物（如PRTN 3、MPO、神经弹性蛋白酶、组织蛋白酶G和嗜酸性粒细胞过氧化物酶）的表达降低。在Cited 2（-/-）Lin（-）c-Kit（+）细胞中也观察到Bmi-1、Notch 1、LEF-1、Mcl-1和GATA 2表达降低。本研究首次揭示了Cited 2在胚胎发育过程中维持造血稳态的新作用，从而为造血发育的分子调控提供了新的见解。
Cited2 (cAMP-responsive element-binding protein [CBP]/p300-interactlng 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(-)cKit(+)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 that received a transplant of Cited2(-/-) fetal liver cells. Competitive reconstitution experiments further showed that fetal liver hematopoietic stem cell (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.