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Updated: Jul 20, 2026
Caspase-3 Activity in the Rat Amygdala Measured by Spectrofluorometry After Myocardial Infarction
Published on: January 12, 2016
Differential regulation of caspase-3 by pharmacological and developmental stimuli as demonstrated using humanised
L E Kerr1, J-L A Birse-Archbold, A Simon
1Fujisawa Institute of Neuroscience in Edinburgh, University of Edinburgh, EH8 9JZ, UK. Lorraine.Kerr@ed.ac.uk
Abstract:
Caspase-3 is a potential therapeutic target for a number of degenerative diseases. However the development of specific caspase-3 inhibitors has been hampered by inter-species differences and the high degree of homology shared by different caspases. To circumvent these issues, we have produced and characterised a humanised caspase-3 mouse line (possessing one copy of the human gene with both copies of the murine gene disrupted) by crossing human caspase-3 transgenic mice with nullizygous caspase-3 knock-out mice. Humanised mice appeared normal and survived to adulthood. Analysis of the human gene revealed that human pro-caspase-3 was expressed in the same tissues as its murine counterpart. However humanised mice retained the hypercellularity of frontal cortex seen in their knock-out parental line and there was no biochemical evidence of human protein processing during naturally occurring neuronal death taking place during brain development. In contrast, the human protein was cleaved by the mouse machinery following anti-Fas treatment of adult mice. These data suggest that there is a fundamental difference between the activation pathways leading to caspase-3 cleavage during naturally occurring cell death in development/embryogenesis and following an apoptotic stimulus in the adult.
Insights
Developing caspase-3 inhibitors is challenging due to species differences. A humanized mouse model showed human caspase-3 is processed differently during development versus adult apoptosis.
Area of Science:
- Biochemistry
- Genetics
- Neuroscience
Background:
- Caspase-3 is a key target for treating degenerative diseases.
- Developing specific caspase-3 inhibitors is difficult due to inter-species variations and caspase homology.
Purpose of the Study:
- To create and characterize a humanized caspase-3 mouse model to overcome challenges in developing caspase-3 inhibitors.
- To investigate the processing and activation of human caspase-3 in vivo.
Main Methods:
- Generated a humanized caspase-3 mouse line by crossing human caspase-3 transgenic mice with caspase-3 knock-out mice.
- Analyzed human pro-caspase-3 expression patterns.
- Assessed human caspase-3 cleavage during natural development and following anti-Fas induced apoptosis.
Main Results:
- Humanized mice were viable and expressed human pro-caspase-3 in tissues similar to murine caspase-3.
- Humanized mice exhibited frontal cortex hypercellularity, similar to knock-out mice.
- Human caspase-3 was not processed during natural developmental neuronal death but was cleaved following anti-Fas treatment in adults.
Conclusions:
- Human caspase-3 processing differs between natural developmental cell death and adult apoptotic stimuli.
- The humanized mouse model provides a platform for studying human caspase-3 activation pathways.
- Activation mechanisms of caspase-3 vary significantly depending on the cellular context and stimulus.
