Delineation of the cell-extrinsic apoptosis pathway in the zebrafish

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.

Early Diversification of the TNF Superfamily in Teleosts: Genomic Characterization and Expression Analysis

“…The presence of multiple forms of TNF-␣, LIGHT, BALM, and TNF-New suggests that redundant and/or divergent systems are tolerated within salmonids. In teleosts, TRAIL-like molecules are particularly complex as we have identified four related genes in Zebrafish in agreement with recently published findings from Eimon et al (23).…”

“…In humans, there is only a single TRAIL gene while two genes have been identified in chickens. In this study, we identify as many as four TRAIL-like genes in Zebrafish in agreement with a recent sequence and functional analyses by Emion et al (23). Synteny analysis of Fugu and Tetraodon both showed serine/threonine protein kinase, cohesin subunit SA stromal Ag SCC3 homolog, propionyl CoA carboxylase, and Zn-finger genes located downstream of Fugu TRAIL-like and Tetraodon TRAIL-like v2 with the same orientation, except for serine/threonine protein kinase (Fig.…”

The role of survivin2 in primitive hematopoiesis during zebrafish development

“…Notwithstanding these limitations, results from the present study have provided us with further leads into the study of apoptosis during embryonic hematopoiesis. In particular, we 12 and others 23 have previously reported the role of death receptor in modulating primitive hematopoiesis. Therefore, how the proapoptotic and antiapoptotic signals integrate to regulate embryonic hematopoiesis would warrant further study.…”

New insights into apoptosis signaling by Apo2L/TRAIL

“…This ligandreceptor pathway is well conserved throughout vertebrate evolution. In zebrafish, the Apo2L/TRAIL pathway is not crucial for proper embryonic development but capable of triggering apoptosis in cells of the erythroid lineage (Eimon et al, 2006). In contrast to humans, mice possess only one cognate DR for Apo2L/ TRAIL, dubbed mDR5 (or mTRAILR2 and mKIL-LER), which shares a similar degree of homology with human DR4 and DR5 (Wu et al, 1999).…”