BAX PROMOTES NEURONAL CELL-DEATH AND IS DOWN-REGULATED DURING THE DEVELOPMENT OF THE NERVOUS-SYSTEM

The Bcl-2 and Bcl-x proteins suppress programmed cell death, whereas B ar promotes apoptosis, We investigated the pattern of expression of Bc l-2, Bar and Bcl-x during neuronal differentiation and development, Al l three proteins were widely expressed in neonatal rats but, in the ad ult, Bar levels were 20- to 140-fold lower in the cerebral cortex, cer ebellum and heart muscle, whereas Bcl-x was not downregulated in any o f the tissues examined, In the cerebral cortex and cerebellum, the dec rease in Bar levels occurred after the period of developmental cell de ath. Further, microinjection of a Bar expression vector into cultured sympathetic neurons, which depend on nerve growth factor for survival, induced apoptosis in the presence of survival factor and increased th e rate of cell death after nerve growth factor withdrawal. This effect could be blocked by co-injection of an expression vector for Bcl-xL o r for the baculovirus p35 protein, an inhibitor of caspases (ICE-like proteases). These results suggest that, during development, the sensit ivity of neurons to signals that induce apoptosis may be regulated by modulating Bar levels and that Bar-induced death requires caspase acti vity.