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J Neuropathol Exp Neurol. 2002 Aug;61(8):673-7.

Strain-dependent neurodevelopmental abnormalities in caspase-3-deficient mice.

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Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.


Targeted gene disruptions have revealed significant roles for caspase family members in the regulation of neuronal programmed cell death. Both caspase-3- and caspase-9-deficient mice exhibit a variably severe neurodevelopmental phenotype that may include marked ventricular zone expansion, exencephaly, and ectopic neuronal structures. Our previous studies of caspase-3- and caspase-9-deficient mice were performed using mice on mixed genetic backgrounds, raising the possibility that strain-specific generic factors influence the effects of caspase deficiency on nervous system development. To directly test this hypothesis. we backcrossed the caspase-3 mutation for 7-10 generations onto pure C57BL/6J and 129X1/SvJ genetic backgrounds. Caspase-3-deficient 129X1/SvJ mice were uniformly and severely affected. These mice died during the perinatal period and exhibited marked neural precursor cell expansion and exencephaly. In contrast, caspase-3-deficient C57BL/6J mice reached adulthood, were fertile and showed minimal brain pathology. Intercrosses of C57BL/6J and 129X1/SvJ mutants revealed that the vast majority of caspase-3-/- F1 mice displayed the severe 129X1/SvJ-"like" phenotype. These findings are consistent with an incompletely penetrant strain-dependent genetic modifier (or modifiers) that alters the neurodevelopmental consequences of caspase-3 deficiency. Since caspase-9- and Apaf-1-deficient mice also display variably severe developmental neuropathology, this strain-dependent modifier(s) may be involved in the activation of a caspase-independent death pathway; alternatively, strain-dependent compensatory caspase activation and/or its inhibition may influence the severity of the caspase-3-deficient neuronal phenotype.

[Indexed for MEDLINE]

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