Roffler-Tarlov S, Brown J J, Tarlov E, Stolarov J, Chapman D L, Alexiou M, Papaioannou V E
Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA.
Development. 1996 Jan;122(1):1-9. doi: 10.1242/dev.122.1.1.
Programmed cell death, or apoptosis, is a normal process in the development of a variety of embryonic and adult tissues, and is also observed in several pathological conditions. Several recent studies, using both expression and functional assays, have implicated the transcription factor, AP-1, in the regulation of programmed cell death, and specifically implicate the genes c-fos and c-jun, as well as some other family members. If the products of the c-fos and/or c-jun genes are essential components in the cascade of events that leads to programmed cell death in mammalian cells, it follows that cell death would not occur in mice lacking functional copies of these genes. We have made use of null mutations in the c-fos and c-jun genes that were produced by gene targeting (Johnson, R.S., Spiegelman, B.M. and Papaioannou, V.E. (1992). Cell 71, 577-586; Johnson, R.S., Van Lingen, B., Papaioannou, V.E. and Spiegelman, B.M. (1993). Genes Dev. 7, 1309-1317) to investigate this possibility. Cell death was assayed using an in situ apoptosis assay in c-fos null embryos and adults, c-jun null embryos, and c-fos/c-jun double null embryos compared with control mice. The occurrence of cell death in c-fos null mice was also assessed in two experimental conditions that normally lead to neuronal cell death. The first was unilateral section of the sciatic nerve in neonates, which leads to the death of anterior horn cells of the spinal cord on the operated side. The second was a genetic cross combining the weaver mutation, which causes death of cerebellar granule cells, with the c-fos mutation. Our results show that programmed cell death occurs normally in developing embryonic tissues and adult thymus and ovary, regardless of the absence of a functional c-fos gene. Furthermore, absence of c-fos had no effect on neuronal cell death in the spinal cord following sciatic nerve section, or in heterozygous weavers' cerebellae. Finally, the results show that programmed cell death can take place in embryos lacking both Fos and Jun.
程序性细胞死亡，即细胞凋亡，是多种胚胎组织和成年组织发育过程中的正常现象，在一些病理状态下也可观察到。最近的几项研究，通过表达分析和功能检测，表明转录因子AP-1参与程序性细胞死亡的调控，特别是涉及c-fos和c-jun基因以及其他一些家族成员。如果c-fos和/或c-jun基因的产物是导致哺乳动物细胞程序性死亡的一系列事件中的关键成分，那么缺乏这些基因功能拷贝的小鼠就不会发生细胞死亡。我们利用基因打靶产生的c-fos和c-jun基因的无效突变（约翰逊，R.S.，斯皮格尔曼，B.M.和帕帕约安努，V.E.（1992年）。《细胞》71卷，577 - 586页；约翰逊，R.S.，范·林根，B.，帕帕约安努，V.E.和斯皮格尔曼，B.M.（1993年）。《基因与发育》7卷，1309 - 1317页）来研究这种可能性。与对照小鼠相比，使用原位凋亡检测法对c-fos基因敲除胚胎和成年个体、c-jun基因敲除胚胎以及c-fos/c-jun双基因敲除胚胎进行细胞死亡检测。还在两种通常会导致神经元细胞死亡的实验条件下评估c-fos基因敲除小鼠中细胞死亡的发生情况。第一种是新生小鼠坐骨神经的单侧切断，这会导致手术侧脊髓前角细胞死亡。第二种是将导致小脑颗粒细胞死亡的weaver突变与c-fos突变进行遗传杂交。我们的结果表明，无论功能性c-fos基因是否缺失，程序性细胞死亡在发育中的胚胎组织以及成年胸腺和卵巢中都正常发生。此外，c-fos基因缺失对坐骨神经切断后脊髓中的神经元细胞死亡或杂合子weaver小鼠的小脑中的神经元细胞死亡没有影响。最后，结果表明程序性细胞死亡可以在同时缺乏Fos和Jun的胚胎中发生。
