Three dominant second-chromosome rearrangement mutations in Drosophila melanogaster, Aristapedioid1 (Arp), vestigial-Depilate (vgD), and vestigial62 (vg62), result in developmental abnormalities of the bristle sense organs on the notum, abdomen, legs, and wing margin. The bristle abnormalities are associated with overexpression of Suppressor 2 of zeste (Su(z)2). We constructed and transformed into flies Hsp70:cDNA constructs for Su(z)2 and the related and neighboring Polycomb group (Pc-G) gene Posterior Sex Combs (Psc). Heat shock-induced overexpression of these two genes (hs-Su(z)2 and hs-Psc) resulted in similar bristle abnormalities that in a developmental stage-specific manner mimicked those seen with the three rearrangement mutations. In addition, hs-Psc overexpression at white prepupae was lethal. The bristle abnormalities are reminiscent of those seen with reduced function of Notch, a neurogenic gene. We found that hs-Su(z)2 overexpression reduced the expression of a lac z enhancer trap in the neurogenic gene neuralized. Previous experiments found that loss of function mutations in Su(z)2 resulted in no bristle abnormalities. Analysis of Psc mitotic clones revealed no essential function of Psc in bristle development. Antibody staining of salivary gland polytene chromosomes showed that after heat shock induction of hs-Psc, Psc protein binds ectopically to hundreds of polytene chromosome loci. These data suggest that the bristle abnormalities seen with overexpression of Su(z)2 and Psc may result from altered expression of genes involved in bristle sense organ development that are not normal regulatory targets of these genes.