Identification and Characterization of Novel Genes by Reverse and Forward Genetics in Zebrafish

Abstract

In summary, we show in chapter 2 that galectin-1 is a receptor for the angiogenesis inhibitor anginex and knock-down of galectin-1 in zebrafish leads to blood vessel guidance and branching defects. In addition, a significant reduction of tumor growth was observed in galectin-1 knock-out mice, suggesting galectin-1 as a target for angiostatic cancer therapy. In chapter 3 we show that mutations in the laminin, integrin and ILK system results in dilation of cardiomyocytes as well as dilation and loss of endothelial cells, providing a new genetic basis for dilated cardiomyopathy in humans. In chapter 4 we show that laminin-induced localization of Ilk at myotendinous junctions connects the ECM via integrin alpha7beta1 with the actin cytoskeleton, thereby strengthening zebrafish skeletal muscle attachments. Furthermore, genetic interaction studies indicate that Ilk acts in parallel with dystroglycan, revealing Ilk as a possible new factor involved in muscular dystrophy. In contrast to invertebrate studies, the suggested ATP binding site of zebrafish Ilk is essential for its in vivo function. In chapter 5 we describe the isolation, mapping and cloning of a zebrafish ubiad1-null mutant, encoding a protein with a prenyltransferase-containing domain. Loss of Ubiad1 in zebrafish resulted in severe blood vessel regression and endothelial cell fragmentation, suggesting a function of Ubiad1 in the maintenance of blood vessels. Is there a link between galectin-1, ubiad