COP9 signalosome regulates EGFR and Notch signaling during myeloid-type progenitor cell fate decision in Drosophila.

The COP9 signalosome (CSN) plays crucial roles in various cellular processes, including cell proliferation and DNA repair, by regulating Cullin-RING ubiquitin ligases that influence protein stability. However, the mechanism by which CSN regulates multiple signaling pathways in stem and progenitor cells for different cell fate decisions remains elusive. Here, we examine the role of the CSN in determining the fate of blood progenitors within the developing Drosophila larval hematopoietic organ, the lymph gland, using in vivo genetics and cell biological methods. We find that CSN-deneddylated, inactive Cullin-1 regulates the differentiation of intermediate progenitors in the lymph glands to generate a correct ratio of plasmatocytes and crystal cells. CSN also controls Serrate activation, which triggers Notch signaling in neighboring cells, leading them to become crystal cells. Moreover, CSN modulates epidermal growth factor receptor (EGFR) signaling, which regulates Notch signaling in intermediate progenitors. Our study reveals that CSN-mediated regulation of EGFR and Notch signaling is crucial for determining the cell fate of myeloid-type blood progenitors, making the lymph gland a convenient model to understand human disease caused by dysregulated EGFR and Notch signaling.