Johnson E M, Deckwerth T L
Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110.
Annu Rev Neurosci. 1993;16:31-46. doi: 10.1146/annurev.ne.16.030193.000335.
Data derived from several experimental approaches demonstrate that naturally occurring neuronal death during development has many parallels with the physiologically appropriate death seen in nonneuronal cells. Physiologically appropriate death in different cell types may share some common mechanisms. These general notions must remain vague and tentative, because details of the mechanisms by which cells die in response to physiological positive or negative signals are poorly understood in any cell type. Current thinking focuses on the idea that cells possess a mechanism, which involves specific gene products, that are designed to kill the cell in response to appropriate physiological signals. Genetic studies of cell death in C. elegans and the demonstrations of increased expression of specific genes temporally associated with death in nonneuronal cells are consistent with this view. However, in the latter studies, there is no direct evidence that such temporally related genes are critical to the process of cell death or whether such gene expression may be related to somE other aspect of the response to the hormonal manipulations that produce the death of the cell under study. Therefore, the mechanism of death of any cell type is not understood, and whether neuronal death during development or after experimental manipulation results from the same mechanism is unknown. Several approaches are currently being pursued in a number of laboratories to address this general problem. These include pharmacological studies, such as described above, and studies aimed at analyzing biochemical and morphological changes associated with death. Attempts to find mRNAs or proteins whose increased expression is associated with neuronal death can be addressed by subtractive and differential hybridization strategies, by two-dimensional protein gel electrophoresis, and by examining genes whose increased expression is temporally correlated with cell death. Success in these various strategies will provide an understanding of neuronal death and relate to it cell death in other cell types. If future work provides direct evidence for a genetic program acting physiologically to produce death in the developing nervous system, an obvious question becomes the possible role that loss of transcriptional control of such a program plays in the adult in responses to mechanical or chemical trauma, neurodegenerative disease, or neuronal attrition associated with aging. Studies addressing the basic developmental process of trophic factor deprivation-induced death should provide molecular markers of and pharmacological approaches to these pathological processes in the adult.
来自多种实验方法的数据表明，发育过程中自然发生的神经元死亡与非神经元细胞中所见的生理上适当的死亡有许多相似之处。不同细胞类型中生理上适当的死亡可能共享一些共同机制。这些一般概念必须保持模糊和暂定，因为在任何细胞类型中，细胞响应生理正或负信号而死亡的机制细节都了解甚少。当前的思考集中在这样一种观点上，即细胞拥有一种机制，该机制涉及特定的基因产物，旨在响应适当的生理信号杀死细胞。秀丽隐杆线虫细胞死亡的遗传研究以及非神经元细胞中与死亡时间相关的特定基因表达增加的证明与这一观点一致。然而，在后者的研究中，没有直接证据表明这种时间相关基因对细胞死亡过程至关重要，或者这种基因表达是否可能与对导致所研究细胞死亡的激素操纵的反应的某些其他方面有关。因此，任何细胞类型的死亡机制都不清楚，发育过程中或实验操作后神经元死亡是否由相同机制导致也未知。目前许多实验室正在采用几种方法来解决这个一般性问题。这些方法包括上述的药理学研究以及旨在分析与死亡相关的生化和形态学变化的研究。通过消减杂交和差异杂交策略、二维蛋白质凝胶电泳以及检查其表达增加与细胞死亡时间相关的基因，可以尝试寻找其表达增加与神经元死亡相关的mRNA或蛋白质。这些各种策略的成功将有助于理解神经元死亡，并将其与其他细胞类型中的细胞死亡联系起来。如果未来的工作为在发育中的神经系统中生理作用导致死亡的遗传程序提供直接证据，一个明显的问题就变成了这种程序转录控制的丧失在成体中对机械或化学创伤、神经退行性疾病或与衰老相关的神经元损耗的反应中可能起的作用。解决营养因子剥夺诱导死亡的基本发育过程的研究应该为这些成体病理过程提供分子标记和药理学方法。
