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Defects in regulation of apoptosis in caspase-2-deficient mice
L Bergeron1, G I Perez, G Macdonald
1Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Abstract:
During embryonic development, a large number of cells die naturally to shape the new organism. Members of the caspase family of proteases are essential intracellular death effectors. Herein, we generated caspase-2-deficient mice to evaluate the requirement for this enzyme in various paradigms of apoptosis. Excess numbers of germ cells were endowed in ovaries of mutant mice and the oocytes were found to be resistant to cell death following exposure to chemotherapeutic drugs. Apoptosis mediated by granzyme B and perforin was defective in caspase-2-deficient B lymphoblasts. In contrast, cell death of motor neurons during development was accelerated in caspase-2-deficient mice. In addition, caspase-2-deficient sympathetic neurons underwent apoptosis more effectively than wild-type neurons when deprived of NGF. Thus, caspase-2 acts both as a positive and negative cell death effector, depending upon cell lineage and stage of development.
Insights
Caspase-2 deficiency in mice impacts cell death pathways differently across various cell types. This protease acts as both a promoter and inhibitor of apoptosis, depending on the cell lineage and developmental stage.
Area of Science:
- Cell Biology
- Developmental Biology
- Genetics
Background:
- Apoptosis, or programmed cell death, is crucial for embryonic development and organismal homeostasis.
- Caspases are key proteases that execute apoptosis, but the specific roles of each caspase are not fully understood.
- Caspase-2 is a member of the caspase family implicated in cell death, but its precise functions remain debated.
Purpose of the Study:
- To investigate the role of caspase-2 in various physiological and pathological apoptotic processes.
- To determine if caspase-2 acts as a pro-apoptotic or anti-apoptotic factor in different cellular contexts.
- To elucidate the developmental and cell-type-specific functions of caspase-2.
Main Methods:
- Generation of caspase-2-deficient mice.
- Analysis of germ cell apoptosis in ovaries of mutant mice.
- Assessment of granzyme B/perforin-mediated apoptosis in B lymphoblasts.
- Evaluation of motor neuron and sympathetic neuron apoptosis during development and in response to NGF deprivation.
Main Results:
- Caspase-2 deficient mice exhibited excess germ cells in ovaries, with oocytes resistant to drug-induced cell death.
- Apoptosis was impaired in caspase-2 deficient B lymphoblasts when mediated by granzyme B and perforin.
- Conversely, motor neuron cell death during development was accelerated in caspase-2 deficient mice.
- Caspase-2 deficient sympathetic neurons showed enhanced apoptosis upon NGF withdrawal.
Conclusions:
- Caspase-2 plays a dual role in apoptosis, acting as both a positive and negative regulator.
- The function of caspase-2 in cell death is dependent on the specific cell lineage and developmental stage.
- These findings highlight the complex and context-dependent nature of caspase-mediated apoptosis.