OVEREXPRESSION OF BCL-2 IN TRANSGENIC MICE PROTECTS NEURONS FROM NATURALLY-OCCURRING CELL-DEATH AND EXPERIMENTAL-ISCHEMIA

Naturally occurring cell death (NOCD) is a prominent feature of the de veloping nervous system. During this process, neurons express bcl-2, a major regulator of cell death whose expression may determine whether a neuron dies or survives. To gain insight into the possible role of b cl-2 during NOCD in vivo, we generated lines of transgenic mice in whi ch neurons overexpress the human BCL-2 protein under the control of th e neuron-specific enolase (NSE) or phosphoglycerate kinase (PCK) promo ters. BCL-2 overexpression reduced neuronal loss during the NOCD perio d, which led to hypertrophy of the nervous system. For instance, the f acial nucleus and the ganglion cell layer of the retina had, respectiv ely, 40% and 50% more neurons than normal. Consistent with this findin g, more axons than normal were found in the facial and optic nerves. W e also tested whether neurons overexpressing BCL-2 were more resistant to permanent ischemia induced by middle cerebral artery occlusion; in transgenic mice, the volume of the brain infarction was reduced by 50 % as compared with wildtype mice. These animals represent an invaluabl e tool for studying the effects of increased neuronal numbers on brain function as well as the mechanisms that control the survival of neuro ns during development and adulthood.