1. ¹Department of Molecular Oncology, Genentech Inc., South San Francisco, CA, USA
2. ²Department of Bioinformatics, Genentech Inc., South San Francisco, CA, USA
3. ³Department of Pathology, Genentech Inc., South San Francisco, CA, USA
4. ⁴The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia

Correspondence: A Ashkenazi, Department of Molecular Oncology, Genentech Inc., 1 DNA Way, MS 42, 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

Members of the Bcl-2 protein family control the intrinsic apoptosis pathway. To evaluate the importance of this family in vertebrate development, we investigated it in the zebrafish (Danio rerio). We found that the zebrafish genome encodes structural and functional homologs of most mammalian Bcl-2 family members, including multi-Bcl-2-homology (BH) domain proteins and BH3-only proteins. Apoptosis induction by -irradiation required zBax1 and zPuma, and could be prevented by overexpression of homologs of prosurvival Bcl-2 family members. Surprisingly, zebrafish Bax2 (zBax2) was homologous to mammalian Bax by sequence and synteny, yet demonstrated functional conservation with human Bak. Morpholino knockdown of both zMcl-1a and zMcl-1b revealed their critical role in early embryonic zebrafish development, and in the modulation of apoptosis activation through the extrinsic pathway. These data indicate substantial functional similarity between zebrafish and mammalian Bcl-2 family members, and establish the zebrafish as a relevant model for studying the intrinsic apoptosis pathway.