Knockdown of PR-DUB subunit calypso in the developing Drosophila eye and wing results in mis-patterned tissues with altered size and shape.

The deubiquitinating enzyme BAP1 is the catalytic subunit of the Polycomb Repressive Deubiquitinase (PR-DUB) complex, which acts with the Polycomb Repressive Complexes 1 and 2 to regulate chromatin organization to repress homeotic genes and other developmental regulators. Loss of BAP1 is implicated in several cancers, in the familial cancer syndrome BAP1 Tumor Predisposition Syndrome, and in the neurodevelopmental disorder Küry-Isidor syndrome. In Drosophila, there are numerous reports in the literature describing developmental patterning phenotypes for several chromatin regulators, including the discovery of Polycomb itself, but corresponding adult morphological phenotypes due to developmental dysregulation of the Drosophila BAP1 ortholog calypso (caly) are less well-described. We report here that knockdown of caly in the eye and wing produces concomitant chromatin dysregulation phenotypes. RNAi to caly in the early eye reduces survival and leads to changes in eye size and shape including eye outgrowths, some of which resemble homeotic transformations, whereas others resemble tumor-like outgrowths seen in other fly cancer models. Mosaic eyes containing caly loss-of-function tissue phenocopy caly RNAi. Knocking down caly across the wing disrupts wing shape and patterning, including effects on wing vein pattern. This phenotypic characterization reinforces the growing body of literature detailing developmental mis-patterning driven by chromatin dysregulation and serves as a baseline for future mechanistic studies to understand the role of BAP1 in development and disease.