Wagner K U, Claudio E, Rucker E B, Riedlinger G, Broussard C, Schwartzberg P L, Siebenlist U, Hennighausen L
Laboratory of Genetics and Physiology, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bldg. 8, Rm. 107, Bethesda, MD 20892-0822, USA.
Development. 2000 Nov;127(22):4949-58. doi: 10.1242/dev.127.22.4949.
Bcl-x is a member of the Bcl2 family and has been suggested to be important for the survival and maturation of various cell types including the erythroid lineage. To define the consequences of Bcl-x loss in erythroid cells and other adult tissues, we have generated mice conditionally deficient in the Bcl-x gene using the Cre-loxP recombination system. The temporal and spatial excision of the floxed Bcl-x locus was achieved by expressing the Cre recombinase gene under control of the MMTV-LTR. By the age of five weeks, Bcl-x conditional mutant mice exhibited hyperproliferation of megakaryocytes and a decline in the number of circulating platelets. Three-month-old animals suffered from severe hemolytic anemia, hyperplasia of immature erythroid cells and profound enlargement of the spleen. We demonstrate that Bcl-x is only required for the survival of erythroid cells at the end of maturation, which includes enucleated reticulocytes in circulation. The extensive proliferation of immature erythroid cells in the spleen and bone marrow might be the result of a fast turnover of late red blood cell precursors and accelerated erythropoiesis in response to tissue hypoxia. The increase in cell death of late erythroid cells is independent from the proapoptotic factor Bax, as demonstrated in conditional double mutant mice for Bcl-x and Bax. Mice conditionally deficient in Bcl-x permitted us for the first time to study the effects of Bcl-x deficiency on cell proliferation, maturation and survival under physiological conditions in an adult animal.
Bcl-x是Bcl2家族的成员，有人认为它对包括红细胞谱系在内的各种细胞类型的存活和成熟很重要。为了确定Bcl-x缺失对红细胞和其他成年组织的影响，我们使用Cre-loxP重组系统构建了Bcl-x基因条件性缺陷的小鼠。通过在MMTV-LTR的控制下表达Cre重组酶基因，实现了对floxed Bcl-x基因座的时空切除。到五周龄时，Bcl-x条件性突变小鼠表现出巨核细胞过度增殖和循环血小板数量下降。三个月大的动物患有严重的溶血性贫血、未成熟红细胞增生和脾脏明显肿大。我们证明，Bcl-x仅在成熟末期的红细胞存活中是必需的，这包括循环中的去核网织红细胞。脾脏和骨髓中未成熟红细胞的广泛增殖可能是晚期红细胞前体快速更新和对组织缺氧反应性红细胞生成加速的结果。如在Bcl-x和Bax的条件性双突变小鼠中所示，晚期红细胞细胞死亡的增加与促凋亡因子Bax无关。Bcl-x条件性缺陷的小鼠首次使我们能够在成年动物的生理条件下研究Bcl-x缺陷对细胞增殖、成熟和存活的影响。
