Divinations and surprises: genetic analysis of caspase function in mice
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Published on: February 1, 2018
1Biogen, Inc., Department of Inflammation, Immunology and Cell Biology, 14 Cambridge Center, Cambridge, Massachusetts 02142, USA. timothy_zheng@biogen.com
Abstract:
Caspases are critical mediators of apoptosis, the principle mechanism by which extra and harmful cells are eliminated to ensure proper development and maintain cellular homeostasis in all multicellular organisms. While compelling evidence suggests that the activation of these otherwise latent intracellular proteases is required for the execution of most, if not all apoptosis in mammals, the presence of more than a dozen caspases presents a major challenge to our understanding of the precise function of individual caspases in vivo. Using a genetic approach, several groups have generated transgenic mice deficient in various caspases so as to investigate their physiological functions. In this review, we will discuss what these studies have revealed about the role of individual caspase in development, apoptosis, and inflammation, with a particular focus on the predictable phenotypes versus the surprises based on in vitro results, as well as the implications of these findings.
Insights
Caspases, key proteases in programmed cell death (apoptosis), have diverse roles in development and inflammation. Genetic studies in mice reveal surprising in vivo functions that differ from in vitro predictions.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- Caspases are essential intracellular proteases that execute apoptosis, a vital process for development and cellular homeostasis in multicellular organisms.
- The large number of caspases (>12) in mammals complicates understanding their specific in vivo functions.
- In vitro studies have provided insights, but in vivo validation is crucial.
Purpose of the Study:
- To review genetic studies investigating the physiological roles of individual caspases in vivo.
- To compare in vivo findings from caspase-deficient mice with in vitro predictions.
- To elucidate the functions of caspases in mammalian development, apoptosis, and inflammation.
Main Methods:
- Review of genetic approaches, specifically the generation and analysis of transgenic mice lacking various caspases.
- Analysis of phenotypes observed in these genetically modified mice.
- Comparison of in vivo data with established in vitro experimental results.
Main Results:
- Genetic ablation of caspases in mice has illuminated their specific roles in development and inflammatory processes.
- Observed in vivo phenotypes often present surprises, diverging from expectations based solely on in vitro enzymatic activity.
- Individual caspases exhibit distinct and sometimes unexpected functions critical for physiological processes.
Conclusions:
- Transgenic mouse models are indispensable for dissecting the in vivo functions of individual caspases.
- In vitro data alone is insufficient to predict the complex physiological roles of caspases.
- Understanding caspase functions in vivo has significant implications for development, apoptosis regulation, and inflammatory diseases.
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