A cautionary tale on genetic screens based on a gain-of-expression approach: The case of LanB1.

Gain of function screens have being frequently used to search for genes affecting a particular adult character or developmental process. These experiments are made possible by the adoption of the Gal4/UAS system to flies, and by the design of P elements bearing UAS sequences. We recently published two screens in which a large number of newly generated P-UAS insertions were crossed with Gal4 drivers expressed in the pupal veins and in the central region of the wing disc. From the data obtained in these and other screens, it seems that a gain-of-function phenotype is a rare occurrence observed only for about 5-8% of insertion sites. Insertions affecting the expression of signaling molecules were particularly enriched in the screens. In contrast, gain-of-function phenotypes due to insertions not belonging to this class appear to be caused by multiple protein-specific mechanisms that could only be unraveled after extensive analysis. We present some data concerning the overexpression of LamB1, a gene encoding the B subunit of Laminin trimers in Drosophila, and show that Notch protein subcellular localization and signaling is compromised in cells overexpressing LanB1.