Functional characterization of the Bcl-2 gene family in the zebrafish

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 c-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.

Expression pattern and transcriptional regulatory mechanism of noxa gene in grass carp (Ctenopharyngodon idella)

“…Noxa, a member of pro-apoptotic proteins belonged to the BCL-2 family, played an important role in the intrinsic apoptosis [11,12]. Many researches about the role of noxa gene in mammalians were reported, but the role and transcriptional regulatory mechanism of noxa in fish were still unclear.…”

“…The intrinsic pathway, also known as mitochondrial pathway, was initiated and regulated by proteins in the BCL-2 family. Up to now, at least 25 proteins including antiapoptotic proteins and pro-apoptotic proteins were found in BCL-2 family, and noxa was one of pro-apoptotic proteins [11,12].…”

“…In zebrafish, Noxa protein was a key mediator of apoptosis in both embryogenesis and adult [18,19]. When the embryos of zebrafish were injected with artificial noxa mRNA, cell apoptosis was observed and the apoptosis was dose-dependent [12]. A significantly up-regulation of noxa mRNA was found in the zebrafish liver cells apoptosis [12,20].…”

Bax, Bcl2, and p53 Differentially Regulate Neomycin- and Gentamicin-Induced Hair Cell Death in the Zebrafish Lateral Line

“…It is possible that the Bax channel inhibitor used in the present study may bind additional targets with unrecognized effects, confounding our results. There is a high degree of functional conservation between mammalian and zebrafish Bcl2 family proteins, suggesting that the Bax channel blocker used here likely interacts with zebrafish Bax (Kratz et al 2006;Jette et al 2008). However, future experiments with genetic Bax manipulation are necessary, particularly since there are two Bax paralogs in zebrafish (Kratz et al 2006).…”

Co-injection strategies to modify radiation sensitivity and tumor initiation in transgenic Zebrafish

“…Noxa is a potent pro-apoptotic BH3-only protein and is a direct transcriptional target of P53 (Oda et al, 2000). The zebrafish noxa ortholog has recently been identified and functionally tested for its ability to induce apoptosis during embryogenesis (Kratz et al, 2006). Given that RAS-induced RMS can be easily visualized in injected animals , tumor onset in wild-type AB-strain animals co-injected with rag2-kRASG12D and rag2-noxa was compared to those injected with rag2-kRASG12D and rag2-dsRED2.…”