Hemp, an mbt domain-containing protein, plays essential roles in hematopoietic stem cell function and skeletal formation
Hemp, an mbt domain-containing protein, plays essential roles in hematopoietic stem cell function and skeletal formation
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DOI：
10.1073/pnas.1003403108
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发表时间：
2011-02-08
影响因子：
11.1
通讯作者：
Lemischka, Ihor R.
中科院分区：
文献类型：
--
作者：
Honda, Hiroaki;Takubo, Keiyo;Lemischka, Ihor R.
为了阐明调控造血干细胞(HSC)发育的分子途径，我们筛选了胎肝(FL)HSC的cDNA文库，并鉴定了一个独特的基因--造血表达的哺乳动物多聚体(HAMP)，该基因编码一个带有锌指结构域和四个恶性脑瘤(MBT)重复序列的蛋白质。为了研究其生物学作用，我们培育了缺乏大麻的小鼠(大麻(-/-))。大麻(-/-)小鼠表现出各种骨骼畸形，并在出生后不久死亡。在FL中，HAMP优先表达于HSC和早期祖细胞，胎儿造血分析显示，在HAMP(-/-)胚胎中，包括HSCs在内的FL单核细胞数量显著减少，尤其是在发育早期。此外，集落形成和竞争性再繁殖实验表明，HEMP(-/-)FL HSCs的增殖和重建能力明显受损。微阵列分析显示，在HAMP(-/-)FL HSCs中，与造血发育和分化有关的几个基因的表达水平发生了变化。这些结果表明，HAMP是一种含有MBT的蛋白质，在HSC功能和骨骼形成中发挥着重要作用。还假设大麻可能与某些先天性疾病有关，例如克利佩尔-费尔畸形。
To clarify the molecular pathways governing hematopoietic stem cell (HSC) development, we screened a fetal liver (FL) HSC cDNA library and identified a unique gene, hematopoietic expressed mammalian polycomb (hemp), encoding a protein with a zinc-finger domain and four malignant brain tumor (mbt) repeats. To investigate its biological role, we generated mice lacking Hemp (hemp(-/-)). Hemp(-/-) mice exhibited a variety of skeletal malformations and died soon after birth. In the FL, hemp was preferentially expressed in the HSC and early progenitor cell fractions, and analyses of fetal hematopoiesis revealed that the number of FL mononuclear cells, including HSCs, was reduced markedly in hemp(-/-) embryos, especially during early development. In addition, colony-forming and competitive repopulation assays demonstrated that the proliferative and reconstitution abilities of hemp(-/-) FL HSCs were significantly impaired. Microarray analysis revealed alterations in the expression levels of several genes implicated in hematopoietic development and differentiation in hemp(-/-) FL HSCs. These results demonstrate that Hemp, an mbt-containing protein, plays essential roles in HSC function and skeletal formation. It is also hypothesized that Hemp might be involved in certain congenital diseases, such as Klippel-Feil anomaly.