Transgenesis and Overexpression of Genes in Annual Fish

Transgenic technology has been recently introduced in zebrafish, and many promoters have been expressed in a tissue-specific manner. Conditional misexpression of genes in certain tissue has been achieved by using GAL4-UAS system (Scheer and Camnos-Ortega, 1999). In this system two different kinds of transgenic strains, called activator and effector lines, are developed. In the activator line, the GAL4 (yeast transcriptional activator) gene is placed under the control of a tissue/cell specific promoter, while in the effector line the gene of interest is fused UAS (Upstream Activating Sequences, the DNA-binding motif of GAL4). Once the effector line is crossed to the activator line, the effector gene is expressed in a specific tissue because the GAL4 is supplied by the tissue specific promoter and will bind to the UAS and drive the effector gene transcription. Recently, the utility of the Cre/lox system has been demonstrated in the zebrafish model by developing a conditional myc-induced T cell acute lymphoblastic leukemia (Langenau et al., 2005). Thus, in addition to GAL4-UAS system, this technology is available for fish. Depending upon the strength of the promoter and taking into account the positional effects, the gene expression could be modulated and the effects on longevity could be studied. Thus, it is conceivable that one could express genes that affect metabolism or oxidative stress pathways or insulin receptor mediated pathways to overexpress these genes. The information gained from studying invertebrate genes could also be used to verify whether mechanisms that are operative in invertebrates are conserved in vertebrates. However, this is a biased approach and would require prior knowledge of the genes that may be involved in lifespan extension. Furthermore, due to the fact that such studies could be performed in mice, one may question the utility of the fish model in such studies. However, since the Nothobranchius is amenable for large-scale unbiased overexpression of genes by using the above vectors that could specifically express genes in certain tissues, with the knowledge of information gained from large scale microarrays depicting the tissue-specific genes, one could construct libraries of such genes and generate transgenic lines on a large scale to verify which ones will have prolonged lifespan. These approaches require further testing.

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