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Published on: June 27, 2011
Delineation of the cell-extrinsic apoptosis pathway in the zebrafish
P M Eimon1, E Kratz, E Varfolomeev
1Department of Molecular Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Abstract:
The mammalian extrinsic apoptosis pathway is triggered by Fas ligand (FasL) and Apo2 ligand/tumor necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL). Ligand binding to cognate receptors activates initiator caspases directly in a death-inducing signaling complex. In Drosophila, TNF ligand binding activates initiator caspases indirectly, through JNK. We characterized the extrinsic pathway in zebrafish to determine how it operates in a nonmammalian vertebrate. We identified homologs of FasL and Apo2L/TRAIL, their receptors, and other components of the cell death machinery. Studies with three Apo2L/TRAIL homologs demonstrated that they bind the receptors zHDR (previously linked to hematopoiesis) and ovarian TNFR (zOTR). Ectopic expression of these ligands during embryogenesis induced apoptosis in erythroblasts and notochord cells. Inhibition of zHDR, zOTR, the adaptor zFADD, or caspase-8-like proteases blocked ligand-induced apoptosis, as did antiapoptotic Bcl-2 family members. Thus, the extrinsic apoptosis pathway in zebrafish closely resembles its mammalian counterpart and cooperates with the intrinsic pathway to trigger tissue-specific apoptosis during embryogenesis in response to ectopic Apo2L/TRAIL expression.
Insights
The zebrafish extrinsic apoptosis pathway, triggered by Apo2 ligand/tumor necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL), closely mirrors the mammalian system. This pathway regulates tissue-specific cell death during embryonic development.
Area of Science:
- Molecular Biology
- Developmental Biology
- Cell Death Pathways
Background:
- The extrinsic apoptosis pathway is crucial for programmed cell death in mammals, initiated by ligands like Fas ligand (FasL) and Apo2 ligand/tumor necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL).
- Mammalian extrinsic apoptosis involves direct activation of initiator caspases via a death-inducing signaling complex upon ligand-receptor binding.
- In contrast, TNF ligand signaling in Drosophila activates initiator caspases indirectly through JNK signaling.
Purpose of the Study:
- To characterize the extrinsic apoptosis pathway in zebrafish, a nonmammalian vertebrate model.
- To determine the functional conservation and operational mechanisms of the extrinsic apoptosis pathway in zebrafish compared to mammals.
Main Methods:
- Identification of zebrafish homologs for key components of the extrinsic apoptosis pathway, including FasL, Apo2L/TRAIL, their receptors, and adaptor proteins.
- Functional analysis using ectopic expression of zebrafish Apo2L/TRAIL homologs during embryogenesis.
- Inhibition studies utilizing genetic or pharmacological approaches targeting receptors (zHDR, zOTR), adaptor proteins (zFADD), caspases, and Bcl-2 family members.
Main Results:
- Zebrafish homologs of Apo2L/TRAIL were identified and shown to bind to receptors zHDR and ovarian TNFR (zOTR).
- Ectopic expression of Apo2L/TRAIL ligands induced apoptosis specifically in erythroblasts and notochord cells during zebrafish embryogenesis.
- Inhibition of key pathway components, including zHDR, zOTR, zFADD, caspase-8-like proteases, and antiapoptotic Bcl-2 proteins, effectively blocked ligand-induced apoptosis.
Conclusions:
- The extrinsic apoptosis pathway in zebrafish shares significant similarities with its mammalian counterpart.
- This pathway plays a role in tissue-specific apoptosis during zebrafish embryogenesis.
- The zebrafish extrinsic apoptosis pathway cooperates with the intrinsic pathway to execute programmed cell death.
Related Concept Videos
01:17The Extrinsic Apoptotic Pathway
01:31The Intrinsic Apoptotic Pathway