title: Strain-dependent neurodevelopmental abnormalities in caspase-3-deficient mice.
abstract: 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.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Leonard
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Klocke
authors.forename: Cleta
authors.initials: C
authors.lastname: D'Sa
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Roth
mesh_terms: D000818:Animals; D053148:Caspase 3; D020169:Caspases / Q000172:deficiency* / Q000235:genetics; D005314:Embryonic and Fetal Development; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout / Q000235:genetics; D009420:Nervous System / Q000196:embryology; D009421:Nervous System Malformations / Q000196:embryology* / Q000235:genetics*; D013045:Species Specificity
chemical_list: C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases