INCREASED INFERIOR OLIVARY NEURON AND CEREBELLAR GRANULE CELL NUMBERSIN TRANSGENIC MICE OVEREXPRESSING THE HUMAN BCL-2 GENE

Neuron-target interactions during development are critical for determi ning the final numbers of neurons in the nervous system. To investigat e the role of Purkinje cells and programmed cell death in the regulati on of afferent neuron numbers, we have counted olivary neurons and gra nule cells in two lines of transgenic mice (NSE73a and NSE71) that ove rexpress a human gene for bcl-2 (Hu-bcl-2) in Purkinje cells and oliva ry neurons, but not in granule cells. Bcl-2 overexpression in vivo red uces naturally occurring neuronal cell death and cell death following axotomy, target removal, or ischemia. Olivary neuron numbers in NSE73a and NSE71 transgenic mice are significantly increased compared to con trols by 28% and 27%, respectively, while granule cell numbers are onl y increased in NSE73a mice (29% above controls). We have previously sh own that Purkinje cell number is increased by 43% in NSE73a transgenic s and by 23% in NSE71 transgenics. The ratio of Purkinje cells to oliv ary neurons is not significantly different between the control and tra nsgenic mice, while the ratio of granule cells to Purkinje cells is si gnificantly decreased in the NSE71 transgenic mice compared to control s and NSE73a transgenics. The increased numbers of olivary neurons sug gest that bcl-2 overexpression rescues these neurons from programmed c ell death. The increase in granule cell number in only one transgenic line is discussed with respect to hypotheses that Purkinje cells regul ate both granule cell progenitor proliferation and the survival of dif ferentiated granule cells. (C) 1997 John Wiley & Sons, Inc.