GATA-2 plays two functionally distinct roles during the ontogeny of hematopoietic stem cells.
GATA-2 plays two functionally distinct roles during the ontogeny of hematopoietic stem cells.
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DOI：
10.1084/jem.20031556
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发表时间：
2004-10-04
期刊：
影响因子：
--
通讯作者：
Dzierzak E
中科院分区：
文献类型：
--
作者：
Ling KW;Ottersbach K;van Hamburg JP;Oziemlak A;Tsai FY;Orkin SH;Ploemacher R;Hendriks RW;Dzierzak E
加塔-2是造血系统中的必需转录因子，其在造血干细胞（HSC）和祖细胞中表达。小鼠中加塔-2的完全缺乏导致严重贫血和胚胎死亡。加塔-2的作用和剂量效应的转录因子在胚胎和成人的HSC发育在很大程度上是未开发的。在这里，我们研究了加塔-2基因剂量对小鼠发育过程中几个造血部位HSC生成和扩增的影响。我们发现，一个单倍体剂量的加塔-2严重减少生产和扩增的HSC，特别是在性腺-中肾区（自主产生的第一个HSC），而定量减少的HSC是最小的或不变的卵黄囊，胎儿肝脏，和成人骨髓。然而，在所有这些个体发育上不同的解剖部位中的HSC在系列或竞争性移植测定中是定性缺陷的。此外，细胞毒性药物诱导的再生研究显示，成人骨髓中存在明显的加塔-2剂量相关性增殖缺陷。因此，加塔-2在HSC的个体发育过程中起至少两种功能上不同的作用：HSC在成体-性腺-中肾中的产生和扩增以及HSC在成体骨髓中的增殖。
GATA-2 is an essential transcription factor in the hematopoietic system that is expressed in hematopoietic stem cells (HSCs) and progenitors. Complete deficiency of GATA-2 in the mouse leads to severe anemia and embryonic lethality. The role of GATA-2 and dosage effects of this transcription factor in HSC development within the embryo and adult are largely unexplored. Here we examined the effects of GATA-2 gene dosage on the generation and expansion of HSCs in several hematopoietic sites throughout mouse development. We show that a haploid dose of GATA-2 severely reduces production and expansion of HSCs specifically in the aorta-gonad-mesonephros region (which autonomously generates the first HSCs), whereas quantitative reduction of HSCs is minimal or unchanged in yolk sac, fetal liver, and adult bone marrow. However, HSCs in all these ontogenically distinct anatomical sites are qualitatively defective in serial or competitive transplantation assays. Also, cytotoxic drug-induced regeneration studies show a clear GATA-2 dose–related proliferation defect in adult bone marrow. Thus, GATA-2 plays at least two functionally distinct roles during ontogeny of HSCs: the production and expansion of HSCs in the aorta-gonad-mesonephros and the proliferation of HSCs in the adult bone marrow.
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