DEFECTIVE HEMATOPOIESIS IN FETAL LIVER RESULTING FROM INACTIVATION OF THE EKLF GENE
DEFECTIVE HEMATOPOIESIS IN FETAL LIVER RESULTING FROM INACTIVATION OF THE EKLF GENE
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DOI：
10.1038/375316a0
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发表时间：
1995-05-25
期刊：
影响因子：
64.8
通讯作者：
GROSVELD, F
中科院分区：
文献类型：
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作者：
NUEZ, B;MICHALOVICH, D;GROSVELD, F
红细胞克虏伯样因子（EKLF）最初是通过鉴别筛选从红细胞RNA中分离出来的，并显示出红细胞特异性，尽管在肥大细胞系中发现了低水平的EKLF（1,2）。EKLF含有三个锌指，与Kruppel转录因子家族中的锌指同源。由于EKLF结合CCACACCCT序列，因此它能够结合β -珠蛋白基因启动子中的CAC盒子，从而影响红细胞的发育（1,2）。该元件的突变导致β -珠蛋白表达减少（3-5），它似乎介导了珠蛋白基因座控制区对启动子的影响(6)。本研究通过在胚胎干细胞中同源重组插入lacZ报告基因，使EKLF基因失活。杂合子EKLF（+/-）小鼠表明，报告基因在胎儿肝脏和成人骨髓的所有类型的红母细胞中以发育特异性的方式表达。纯合子EKLF（-/-）小鼠在卵黄囊造血的胚胎阶段表现正常，但在早期胎儿生命中，当造血转移到胎儿肝脏时，发生致命的贫血。形成去核红细胞，但这些红细胞不含适量的血红蛋白。我们得出结论，转录因子EKLF在胎儿肝脏最终红细胞生成的最后步骤中是必不可少的。
ERYTHROID Kruppel-like factor (EKLF) was originally isolated from erythroid cell RNA by differential screening and shown to be erythroid-specific, although a low level of EKLF was found in mast cell lines(1,2). EKLF contains three zinc-fingers homologous to those found in the Kruppel family of transcription factors, Because it binds the sequence CCACACCCT, EKLF may affect erythroid development as a result of its ability to bind to the CAC box in the promoter of the beta-globin gene(1,2). Mutation of this element leads to reduced beta-globin expression(3-5) and it appears to mediate the effect of the globin locus control region on the promoter(6). Here we inactivate the EKLF gene through insertion of a lacZ reporter gene by homologous recombination in embryonic stem (ES) cells. Heterozygous EKLF(+/-) mice show that the reporter gene is expressed in a developmentally specific manner in all types of erythroblasts in the fetal liver and adult bone marrow. Homozygous EKLF(-/-) mice appear normal during the embryonic stage of haematopoiesis in the yolk sac, but develop a fatal anaemia during early fetal life when haematopoiesis has switched to the fetal liver. Enucleated erythrocytes are formed but these do not contain the proper amount of haemoglobin. We conclude that the transcription factor EKLF is essential for the final steps of definitive erythropoiesis in fetal liver.