Strain-dependent neurodevelopmental abnormalities in caspase-3-deficient mice.
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.
Leonard
Jeffrey R
JR
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Klocke
Barbara J
BJ
D'Sa
Cleta
C
Flavell
Richard A
RA
Roth
Kevin A
KA
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
C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases