Polycomb group (PcG) proteins are conserved epigenetic regulators that maintain targets at a repressed transcription state. In my dissertation research, I generated phdel, the first real null allele of the Drosophila PcG gene polyhomeotic (ph). Using this allele, I found that loss of ph causes cell over-proliferation in mosaic tissues in a non-autonomous manner, meaning that the mutant cells induce over-proliferation of neighboring wild type cells. I further identified the underlying signaling pathways: Notch signaling is elevated autonomously in phdel cells, which causes the over-production of 3 Upd homologs. These ligands are then secreted and activate the JAK/STAT pathway in neighboring cells, which eventually causes cell over-proliferation. In addition, phdel cells maintain normal cell polarity but undergo invagination to form unique 3 dimensional structures. Such structures are morphologically and functionally similar to epithelia-derived endocrine glands.

Interestingly, ph505, another ph allele that has long been considered null, causes both autonomous and non-autonomous cell proliferation in mosaic tissues. To explain the discrepancies between phdel and ph505, I characterized the nature of ph505. Data from embryonic lethal stage, rescue by ph-d, and exon sequencing all showed that ph505 is a hypomorph. Functional analysis then proved that the same signaling pathway also underlies non-autonomous proliferation in ph505 mosaic tissues.

I then showed that ph505 cells still respond to the Upd ligands they secreted, but phdel cell are no longer responsive. This explains why ph505 cells still over-proliferate but phdel cell do not. Next, Real-Time PCR results demonstrated that the JAK/STAT pathway receptor domeless has a higher expression level in ph505 cells than in phdel cells, which may explain their different sensitivities to Upd ligands. Finally, genome wide ChIP data in public database suggest that Notch may be a direct target of Polycomb Repressive Complex 1, in which Ph is a core component.

My dissertation established that loss of ph causes non-autonomous over-proliferation, and elucidated the underlying mechanism. My results also call for a reevaluation of the non-autonomous over-proliferation pathway in Drosophila. Finally, the fact that different alleles of the same gene cause tumors in very different ways have certain implications to cancer research and treatment.