Postnatal Expression ofHu-Bcl-2Gene inLurcherMutant Mice Fails to Rescue Purkinje Cells but Protects Inferior Olivary Neurons from Target-Related Cell Death

Open Access
Publisher Website
Google Scholar
Abstract
TheLurchermutant has been extensively studied as a model for cell-autonomous and target-related cell death, yet there are still many unknowns concerning the mechanisms of neuronal degeneration in this mutant. As a key regulator of apoptosis, abcl-2transgene has been overexpressed in the heterozygousLurchermutant to investigate the effects of BCL-2 on two types ofin vivoneuronal cell loss inLurcher: cell-autonomous Purkinje cell degeneration and target-related olivary neuron death. Six adult +/Lcmutants expressing a humanbcl-2transgene (Hu-bcl-2) were generated by crossing +/Lcmutants with NSE71Hu-bcl-2transgenic mice. Analysis of these brains showed thatbcl-2overexpression did not prevent +/LcPurkinje cell degeneration, but it did rescue most olivary neurons from target-related cell death. Although the number of olivary neurons was equivalent to wild-type numbers, the inferior olive nucleus was significantly shorter in its rostrocaudal extent, suggesting that olivary neurons are atrophied. We propose thatLurchergene action causes Purkinje cell degeneration independently of a BCL-2-mediated pathway. Furthermore, althoughbcl-2overexpression rescues olivary neurons from target-related cell death, it does not prevent the atrophy associated with the loss of target-related trophic support.