Mouse zeta- and alpha-globin genes: Embryonic survival, alpha-thalassemia, and genetic background effects
Mouse zeta- and alpha-globin genes: Embryonic survival, alpha-thalassemia, and genetic background effects
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DOI：
10.1182/blood.v90.3.1275.1275_1275_1282
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发表时间：
1997-08-01
期刊：
影响因子：
20.3
通讯作者：
Leder, P
中科院分区：
文献类型：
--
作者：
Leder, A;Daugherty, C;Leder, P
关于鼠胚胎ζ-和成体α-珠蛋白基因表达的经典概念认为，在胎儿发育期间珠蛋白产生从胚胎形式转换为成体形式。我们以前的原位杂交研究挑战了这一观点，因为在最早的红细胞群体中可以同时检测到ζ-和α-珠蛋白mRNA。这一发现提出了这样的可能性，即ζ-珠蛋白的产生可能在胚胎中完全或部分冗余，其中成人α-珠蛋白也表达。为了测试这种可能性，我们在胚胎干细胞中使用同源重组创建了zeta珠蛋白基因的无效突变。许多zeta-无效突变纯合子的远交小鼠能够正常发育，这破坏了绝对需要zeta-珠蛋白的概念，并表明单独的α-珠蛋白可以满足胎儿的生存需要。有趣的是，将PGK-Neo盒（用于产生无效突变）插入ζ-珠蛋白基因似乎会影响附近α-珠蛋白基因的表达，导致α-珠蛋白产生减少和α-地中海贫血样综合征。还有证据表明遗传背景对zeta无效和α 1无效表型的强烈影响，这两者在129/SvEv近交遗传背景中都严重得多。这些数量上的差异可能被用来鉴定红细胞生成的重要基因。(C)1997年，美国血液学会。
A classical notion regarding the expression of murine embryonic zeta- and adult alpha-globin genes holds that there is a switch in globin production from the embryonic to the adult form during fetal development. Our previous in situ hybridization studies challenged this view, since both zeta- and alpha-globin mRNAs can be detected simultaneously in the earliest erythrocyte populations, This finding raises the possibility that zeta-globin production might be wholly or partially redundant in embryos in which the adult alpha-globin is also expressed. To test this possibility, we created a null mutation of the zeta-globin gene using homologous recombination in embryonic stem cells. Many outbred mice homozygous for the zeta-null mutation were able to develop normally, undermining the notion that there is an absolute need for zeta-globin and indicating that alpha-globin alone can serve the survival needs of the fetus. Interestingly, insertion of the PGK-Neo cassette (used to create the null mutation) into the zeta-globin gene appears to influence the expression of the nearby alpha-globin genes, giving rise to reduced alpha-globin production and to an alpha-thalassemia-like syndrome. There is also evidence indicating the strong influence of genetic background on the zeta-null and alpha 1-null phenotypes, both of which are much more severe in the 129/SvEv inbred genetic background. These quantitative differences can potentially be exploited to identify genes important for erythropoiesis. (C) 1997 by The American Society of Hematology.