Targeted degradation of Drosophila FOG homolog U-shaped mimics macrophage transdifferentiation in S2 cells.

The highly plastic cellular component of the Drosophila immune system consists of three main blood cell types - plasmatocytes, crystal cells and lamellocytes - that together allow effective responses to various insults. Infection with parasitic wasp eggs results in a rapid increase in highly specialized lamellocytes that are generated by differentiation from hemocyte precursors as well as by transdifferentiation from plasmatocytes. How differentiation and transdifferentiation are regulated at the molecular level is not well understood. Here, we show that inducible degradation of the Friend of GATA (FOG) homolog U-shaped (Ush) in the plasmatocyte-like S2 cell line results in downregulation of a significant proportion of plasmatocyte marker genes and subsequent upregulation of a significant proportion of lamellocyte marker genes. This transcriptional shift is accompanied by morphological and functional changes consistent with lamellocyte cell identity, including increased cell spreading, driven by enhanced integrin expression associated with increased focal adhesions. Our findings demonstrate that targeted Ush depletion while not resulting in a complete transdifferentiation into lamellocytes is sufficient to reprogramme plasmatocyte-like S2 cells toward a more lamellocyte-like state, thereby providing a novel opportunity to dissect some of the processes involved in macrophage transdifferentiation.