Genetic Screen for Regulators of Lymph Gland Homeostasis and Hemocyte Maturation in Drosophila

Blood cell development in the Drosophila lymph gland is controlled by multiple factors, most of them conserved from flies to mammals. The Drosophila homolog of vertebrate PDCD2, Zfrp8, is required in Drosophila hematopoietic stem cell development. Zfrp8 mutant larvae show a disruption of homeostasis in the lymph gland and vast lymph gland overgrowth. The loss of one copy of Zfrp8 also causes a lymph gland enlargement. This dominant phenotype can be modified by heterozygous mutations in cell-cycle genes and several genes functioning in blood development. To identify additional genes that function in hematopoiesis, we screened a collection of second and third chromosome deficiencies for modifiers of Zfrp8 heterozygous phenotype. Using deficiency mapping, available single gene mutations, and RNAi lines, we identified several novel factors required for lymph gland development and hemocyte differentiation. Distinct lymph gland phenotypes of nine of these genes are reported here for the first time. Importantly, the orthologs of four of them have a role in mammalian blood development and leukemogenesis. Our work has shown that the number of genes regulating normal blood cell development in Drosophila is much larger than expected, and that the complex molecular mechanisms regulating hemocyte differentiation are comparable to those in vertebrates.