Genetic and Molecular Characterization of Drosophila Brakeless: A Novel Modifier of Merlin Phenotypes

摘要

Scribbler is a dominant second site modifier of the Drosophila Merlin tumor suppressor gene. This year we have described a signal transduction circuit among scribbler, Merlin and Cyclin E. Using genetic epistasis, we show that Merlin functions upstream of both scribbler and Cyclin E - demonstrating that Merlin is a dominant second site repressor of loss of function phenotypes for Cyclin E. We also show that the two scribbler protein isoforms are not functionally equivalent; the smaller SbbA expression promotes ectopic proliferation via ectopic transcription of Cyclin E, while the larger SbbB represses proliferation by reducing the amount of Cyclin E expression. Using these data we have constructed an intriguing pathway for scribbler/Merlin regulation of proliferation. We propose Merlin functions by regulating the intracellular levels of the two scribbler isoforms. As we propose, in cells that are undifferentiated and actively proliferating, the expression of the smaller, proliferagenic SbbA isoform predominates, while in cells that have differentiated, Merlin may down regulate the expression of SbbA and promote the expression of SbbB. Currently we do not know whether Merlin may be regulating alternative splicing or the stability/instability of the mRNA of scribbler isoforms.