MOLECULAR MECHANISMS OF DEVELOPMENTAL NEURONAL DEATH

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.