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The Journal of Neuroscience, November 3, 2004, 24(44):9977-9984; doi:10.1523/JNEUROSCI.3356-04.2004

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Development/Plasticity/Repair
Caspase-7 Expanded Function and Intrinsic Expression Level Underlies Strain-Specific Brain Phenotype of Caspase-3-Null Mice

Caroline Houde,¹ Kathleen G. Banks,² Nathalie Coulombe,³ Dita Rasper,³ Erich Grimm,³ Sophie Roy,^1,4 Elizabeth M. Simpson,² and Donald W. Nicholson^1,4

¹Biochemistry Department, McGill University, Montreal, Quebec H3G 1Y6, Canada, ²Centre for Molecular Medicine and Therapeutics, British Columbia Institute for Children's and Women's Health, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada, ³Merck Frosst Canada and Company, Pointe-Claire-Dorval, Quebec H9R 4P8, Canada, and ⁴Merck Research Laboratories, San Diego, California 92121

Caspase-3-deficient mice of the 129S1/SvImJ (129) strain show severe brain development defects resulting in brain overgrowth and perinatal lethality, whereas on the C57BL/6J (B6) background, these mice develop normally. We therefore sought to identify the strain-dependent ameliorating gene. We biochemically isolated caspase-7 from B6-caspase-3-null (Casp3^-/-) tissues as being the enzyme with caspase-3-like properties and capability of performing a caspase-3 surrogate function, apoptotic DNA fragmentation. Moreover, we show that, in contrast to the human enzymes, mouse caspase-7 is as efficient as caspase-3 at cleaving and thus inactivating ICAD (inhibitor of caspase-activated DNase), the inhibitor of apoptotic DNA fragmentation. Low levels of caspase-7 expression and activation correlate with lack of DNA fragmentation in 129-Casp3^-/- apoptotic precursor neurons, whereas B6-Casp3^-/- cells, which can fragment their DNA, show higher levels of caspase-7 expression and activation. The amount of caspase-7 activation in apoptotic precursor neurons is independent of the presence of caspase-3. Together, our findings demonstrate for the first time a strong correlation between caspase-7 activity, normal brain development, and apoptotic DNA fragmentation in Casp3^-/- mice.

Key words: apoptosis; brain development; strain-specific phenotype; caspase-3 compensation; caspase-7; DNA fragmentation

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Received May 12, 2004; revised September 16, 2004; accepted September 17, 2004.

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