Figure 2: The Overall Approach to In Vivo Chemical Screening in the Zebrafish

2019-06-11T07:03:25Z (GMT) by Aaron Kithcart Calum A. MacRae
Discrete disease models are developed and then screened at tremendous scale. In this context, the throughput of the zebrafish allows in vivo testing of hypotheses using similar levels of brute force to those used in cell-based assays. Indeed, the zebrafish may best be thought of not just as a “simple” in vivo model but also as cell culture but with the recreation of much of the complexity of differentiation and native multicellular context. By normalizing not just the primary defect but multiple interdependent aspects of the disease biology, it is anticipated that the resultant small molecules will address many of the complexities of disease. One such example is highlighted on the right. A compound (SB2) identified in a zebrafish screen for suppressors of a plakoglobin mutant phenotype reduces the ventricular ectopic activity seen in a mouse model of the same desmosomal mutant protein. In addition, the same compound rescues contractile abnormalities (top right) and conduction abnormalities (bottom right) observed in a mouse model of the related disorder caused by mutations in the desmoglein2 gene.