Postnatal Expression of Hu-Bcl-2 Gene inLurcher Mutant Mice Fails to Rescue Purkinje Cells but Protects Inferior Olivary Neurons from Target-Related Cell Death
- 1Laboratoire de Neurobiologie du Développement, Institut des Neurosciences et Unité de Recherche Associée, Centre National de la Recherche Scientifique 1488, UniversitéPierre et Marie Curie, 75005 Paris, France,
- 2Physiological Science Department, University of California at Los Angeles, Los Angeles, California 90095-1527,
- 3Geneva Biomedical Research Institute, Glaxo Wellcome Research and Development SA, 1228 Plan-les-Ouates, Geneva, Switzerland, and
- 4Maryland Psychiatric Research Center, University of Maryland Medical School, Baltimore, Maryland 21228
Abstract
The Lurcher mutant 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, a bcl-2transgene has been overexpressed in the heterozygousLurcher mutant to investigate the effects of BCL-2 on two types of in vivo neuronal cell loss inLurcher: cell-autonomous Purkinje cell degeneration and target-related olivary neuron death. Six adult +/Lcmutants expressing a human bcl-2 transgene (Hu-bcl-2) were generated by crossing +/Lc mutants with NSE71 Hu-bcl-2transgenic mice. Analysis of these brains showed thatbcl-2 overexpression 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 that Lurchergene action causes Purkinje cell degeneration independently of a BCL-2-mediated pathway. Furthermore, although bcl-2overexpression rescues olivary neurons from target-related cell death, it does not prevent the atrophy associated with the loss of target-related trophic support.
- Received May 21, 1997.
- Revision received October 17, 1997.
- Accepted October 22, 1997.
- Copyright © 1998 Society for Neuroscience
