EKLF and KLF2 have compensatory roles in embryonic β-globin gene expression and primitive erythropoiesis
EKLF and KLF2 have compensatory roles in embryonic β-globin gene expression and primitive erythropoiesis
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DOI：
10.1182/blood-2006-11-057307
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发表时间：
2007-11-01
期刊：
影响因子：
20.3
通讯作者：
Lloyd, Joyce A.
中科院分区：
文献类型：
--
作者：
Basu, Priyadarshi;Lung, Tina K.;Lloyd, Joyce A.
Kruppel样C2/H2锌指转录因子（KLF）控制发育和分化。红细胞Kruppel样因子（EKLF或KLF 1）调节成人β-珠蛋白基因表达，是正常的永久性红细胞生成所必需的。KLF 2是正常胚胎Ey-和β h1-所需的，但不是成年β-珠蛋白，基因表达在小鼠。EKLF和KLF 2都在原始红系细胞发育中发挥作用。为了研究这些基因之间的潜在相互作用，分析了EKLF/KLF 2双突变胚胎。EKLF（-/-）KLF 2（-/-）小鼠在胚胎第10.5天（E10.5）出现贫血，并在E11.5之前死亡，而单敲除EKLF-/-或KLF 2（-/-）胚胎在E10.5时大体正常，并晚于EKLF（-/-）KLF 2（-/-）胚胎死亡。E10.5时，EKLF（-/-）KLF 2（-/-）中Ey-和β h1-珠蛋白mRNA的表达显著低于EKLF-/-或KLF 2（-/-）胚胎，这与观察到的贫血一致。E9.5 EKLF（-/-）KLF 2（-/-）卵黄囊和细胞离心涂片的光镜和电镜分析表明，红细胞和内皮细胞在形态上比任何一个单一敲除更异常。EKLF（-/-）KLF 2（-/-）红系细胞形状明显不规则，提示膜异常。EKLF和KLF 2可能在红系细胞和内皮细胞的共同祖细胞中起协调作用。这些数据表明，EKLF和KLF 2在胚胎β样珠蛋白基因表达、原始红细胞生成和内皮发育中具有冗余功能。
The Kruppel-like C2/H2 zinc finger transcription factors (KLFs) control development and differentiation. Erythroid Kruppel-like factor (EKLF or KLF1) regulates adult beta-globin gene expression and is necessary for normal definitive erythropoiesis. KLF2 is required for normal embryonic Ey- and beta h1-, but not adult beta-globin, gene expression in mice. Both EKLF and KLF2 play roles in primitive erythroid cell development. To investigate potential interactions between these genes, EKLF/KLF2 double-mutant embryos were analyzed. EKLF(-/-)KLF2(-/-) mice appear anemic at embryonic day 10.5 (E10.5) and die before E11.5, whereas single-knockout EKLF-/- or KLF2(-/-) embryos are grossly normal at E10.5 and die later than EKLF(-/-)KLF2(-/-) embryos. At E10.5, Ey-and beta h1-globin mRNA is greatly reduced in EKLF(-/-)KLF2(-/-), compared with EKLF-/- or KLF2(-/-) embryos, consistent with the observed anemia. Light and electron microscopic analyses of E9.5 EKLF(-/-)KLF2(-/-) yolk sacs, and cytospins, indicate that erythroid and endothelial cells are morphologically more abnormal than in either single knockout. EKLF(-/-)KLF2(-/-) erythroid cells are markedly irregularly shaped, suggesting membrane abnormalities. EKLF and KLF2 may have coordinate roles in a common progenitor to erythroid and endothelial cells. The data indicate that EKLF and KLF2 have redundant functions in embryonic beta-like globin gene expression, primitive erythropoiesis, and endothelial development.