POSTNATAL EXPRESSION OF HU-BCL-2 GENE IN LURCHER MUTANT MICE FAILS TORESCUE PURKINJE-CELLS BUT PROTECTS INFERIOR OLIVARY NEURONS FROM TARGET-RELATED CELL-DEATH

The Lurcher mutant has been extensively studied as a model for cell-au tonomous and target-related cell death, yet there are still many unkno wns concerning the mechanisms of neuronal degeneration in this mutant. As a key regulator of apoptosis, a bcl-2 transgene has been overexpre ssed in the heterozygous Lurcher mutant to investigate the effects of BCL-2 on two types of in vivo neuronal cell loss in Lurcher: cell-auto nomous Purkinje cell degeneration and target-related olivary neuron de ath. Six adult +/Lc mutants expressing a human bcl-2 transgene (Hu-bcl -2) were generated by crossing +/Le mutants with NSE71 Hu-bcl-2 transg enic mice. Analysis of these brains showed that bcl-2 overexpression d id not prevent +/Lc Purkinje cell degeneration, but it did rescue most olivary neurons from target-related cell death. Although the number o f olivary neurons was equivalent to wild-type numbers, the inferior ol ive nucleus was significantly shorter in its rostrocaudal extent, sugg esting that olivary neurons are atrophied. We propose that Lurcher gen e action causes Purkinje cell degeneration independently of a BCL-2-me diated pathway. Furthermore, although bcl-2 overexpression rescues oli vary neurons from target-related cell death, it does not prevent the a trophy associated with the loss of target-related trophic support.