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The Journal of Neuroscience, January 1, 1998, 18(1):319-327

Postnatal Expression of Hu-Bcl-2 Gene in Lurcher Mutant Mice Fails to Rescue Purkinje Cells but Protects Inferior Olivary Neurons from Target-Related Cell Death

H. S. Zanjani^{1, 2}, M. W. Vogel⁴, J. C. Martinou³, N. Delhaye-Bouchaud¹, and J. Mariani¹

¹ Laboratoire de Neurobiologie du Développement, Institut des Neurosciences et Unité de Recherche Associée, Centre National de la Recherche Scientifique 1488, Université Pierre et Marie Curie, 75005 Paris, France, ² Physiological Science Department, University of California at Los Angeles, Los Angeles, California 90095-1527, ³ Geneva Biomedical Research Institute, Glaxo Wellcome Research and Development SA, 1228 Plan-les-Ouates, Geneva, Switzerland, and ⁴ Maryland Psychiatric Research Center, University of Maryland Medical School, Baltimore, Maryland 21228

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-2 transgene has been overexpressed in the heterozygous Lurcher mutant to investigate the effects of BCL-2 on two types of in vivo neuronal cell loss in Lurcher: cell-autonomous Purkinje cell degeneration and target-related olivary neuron death. Six adult +/Lc mutants expressing a human bcl-2 transgene (Hu-bcl-2) were generated by crossing +/Lc mutants with NSE71 Hu-bcl-2 transgenic mice. Analysis of these brains showed that bcl-2 overexpression did not prevent +/Lc Purkinje 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 Lurcher gene action causes Purkinje cell degeneration independently of a BCL-2-mediated pathway. Furthermore, although bcl-2 overexpression rescues olivary neurons from target-related cell death, it does not prevent the atrophy associated with the loss of target-related trophic support.

Key words: olivary neurons; Purkinje cells; BCL-2; Lurcher mutant; programmed cell death; cerebellar mutants

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Copyright © 1998 Society for Neuroscience  0270-6474/98/181319-09$05.00/0

This article has been cited by other articles:

				F. Selimi, M. W. Vogel, and J. Mariani Bax Inactivation in Lurcher Mutants Rescues Cerebellar Granule Cells But Not Purkinje Cells or Inferior Olivary Neurons J. Neurosci., July 15, 2000; 20(14): 5339 - 5345. [Abstract] [Full Text] [PDF]

				M. L. Doughty, P. L. De Jager, S. J. Korsmeyer, and N. Heintz Neurodegeneration in Lurcher Mice Occurs via Multiple Cell Death Pathways J. Neurosci., May 15, 2000; 20(10): 3687 - 3694. [Abstract] [Full Text] [PDF]

				F. Selimi, M. Doughty, N. Delhaye-Bouchaud, and J. Mariani Target-Related and Intrinsic Neuronal Death in Lurcher Mutant Mice Are Both Mediated by Caspase-3 Activation J. Neurosci., February 1, 2000; 20(3): 992 - 1000. [Abstract] [Full Text] [PDF]

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