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The Journal of Neuroscience, May 15, 2000, 20(10):3687-3694

Neurodegeneration in Lurcher Mice Occurs via Multiple Cell Death Pathways

Martin L. Doughty¹, Philip L. De Jager¹, Stanley J. Korsmeyer³, and Nathaniel Heintz^{1, 2}

¹ Laboratory of Molecular Biology and ² Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10021, and ³ Harvard Medical School, Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts 02115

Lurcher (Lc) is a gain-of-function mutation in the 2 glutamate receptor (GRID2) that results in the cell-autonomous death of cerebellar Purkinje cells in heterozygous lurcher (+/Lc) mice. This in turn triggers the massive loss of afferent granule cells during the first few postnatal weeks. Evidence suggests that the death of Purkinje cells as a direct consequence of GRID2^Lc activation and the secondary death of granule cells because of target deprivation occur by apoptosis. We have used mice carrying null mutations of both the Bax and p53 genes to examine the roles of these genes in cell loss in lurcher animals. The absence of Bax delayed Purkinje cell death in response to the GRID2^Lc mutation and permanently rescued the secondary death of granule cells. In contrast, the p53 deletion had no effect on either cell death pathway. Our results demonstrate that target deprivation induces a Bax-dependent, p53-independent cell death response in cerebellar granule cells in vivo. In contrast, Bax plays a minor role in GRID2^Lc-mediated Purkinje cell death.

Key words: lurcher; cerebellum; Bax; p53; caspase-3; apoptosis

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20103687-08$05.00/0

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