1. ¹Department of Molecular Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA
2. ²Department of Protein Engineering, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA
3. ³Department of Pathology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA

Correspondence: A Ashkenazi, Departments of Molecular Oncology, Protein Engineering, and Pathology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Tel: +650-225-1853; Fax: +650-467-8195; E-mail: aa@gene.com

Received 12 June 2006; Accepted 26 June 2006; Published online 4 August 2006.

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.