A Serrate-expressing signaling center controlsDrosophilahematopoiesis

Abstract

The differentiation of Drosophila blood cells relies on a functional hierarchy between the GATA protein, Serpent (Srp), and multiple lineage-specific transcription factors, such as the AML1-like protein, Lozenge (Lz). Two major branches of Drosophila hematopoiesis give rise to plasmatocytes/macrophages and crystal cells. Serrate signaling through the Notch pathway is critical in the regulation of Lz expression and the specification of crystal cell precursors, thus providing a key distinction between the two lineages. The expression of Serrate marks a discrete cluster of cells in the lymph gland, a signaling center, with functional similarities to stromal signaling in mammalian hematopoiesis. Received November 8, 2002; revised version accepted December 9, 2002. Runx1, also known as Acute Myeloid Leukemia 1 (AML1), is essential for the development of blood cells arising from all lineages of definitive hematopoiesis in mice (Okuda et al. 1996;Wang et al. 1996). In humans, AML1 is the most frequent target for translocations resulting in acute myeloid leukemias (Werner et al. 1999). The family of GATA transcription factors is also used reiteratively in multiple stages of blood development (Orkin 1998), and a cofactor for the GATA proteins, FOG1, is required for erythropoiesis and differentiation of megakaryocytes (Tsang et al. 1998). In studying the regulation of such transcription factors, in vitro differentiation assays have suggested that multiple signaling pathways are coordinately involved in hematopoiesis (Van Den Berg et al. 1998;Yoshida et al. 1998;Milner and Bigas 1999). Unfortunately, there is a paucity of in vivo loss-of-function data involving signaling pathways that control hematopoiesis in mammals due to difficulties such as pleiotropy, redundancy, and early lethality.There are significant differences with regard to the variety and function of Drosophila hemocytes relative to mammalian blood cells, however, several molecular aspects of early hematopoiesis and immunity have been evolutionarily conserved (Rehorn et al. 1996;Dearolf 1998;Hoffmann et al. 1999;Lebestky et al. 2000). Two major classes of Drosophila hemocytes are plasmatocytes, which can function as macrophages that phagocytose invading pathogens and debris from apoptotic cells (Tepass et al. 1994), and crystal cells that are involved in the melanization of pathogens (Rizki et al. 1980). serpent (srp), a Drosophila GATA homolog, is expressed in all hemocyte precursors and is required for the development of both classes of hemocytes (Rehorn et al. 1996;Lebestky et al. 2000). lozenge (lz) encodes an AML1/Runt domain family transcription factor (Daga et al. 1996) that is expressed in the crystal cell precursors and is required for the specification of this lineage (Rizki and Rizki 1981; Lebestky et al. 2000). glial cells missing (gcm), a novel transcription factor expressed exclusively in plasmatocytes in the embryo (Bernardoni et al. 1997), is required for their development. Its possible role in larval hematopoiesis is less clear. Srp is ess...

JAK signaling globally counteracts heterochromatic gene silencing

“…Among the hop Tum-l modifiers identified, several are known to interact with the JAK/STAT pathway or to be involved in blood or tumor formation. These include the human tumor suppressor nm23-H1 homolog abnormal wing discs (awd), Toll, PIAS, NURF301 and Serrate (Ser) (Supplementary Table 1) 7,15,[21][22][23][24] , supporting the specificity of this screen.A major class of E(Tum-l) genes identified in this screen encode proteins involved in chromatin modification. These include HP1, the histone H3-K9 methyltransferase Su(var)3-9, histone deacetylase (HDAC) Rpd3 and several other chromodomain-containing proteins ( Fig.…”

AML1/Runx1 rescues Notch1-null mutation-induced deficiency of para-aortic splanchnopleural hematopoiesis

“…The functional relationship between Notch and Runx families during hematopoietic development was first indicated in Drosophila, in which Notch up-regulates the expression of a Runt family gene, Lozenge. 10 More recently, it was shown that a zebrafish Notchsignaling mutant mind bomb fails in the specification of definitive HSCs during embryogenesis, and that Runx1 is required for expansion of HSCs in the zebrafish AGM region sufficient to restore the HSC specification in the mind bomb mutant. 11 The data shown in the present study strongly indicate that the Notch-Runx pathway is conserved from invertebrates to mammals and that Runx1 locates at a very proximal position in the Notch1 signaling pathway during establishment of definitive hematopoiesis.…”

“…10,11 We thus first evaluated whether Notch activation results in up-regulation of Runx1 also in the mammalian system. When NIH3T3 cells were transiently transfected with Notch1 intracellular domain (NICD), which represents the constitutive active form of Notch1, the mRNA level of Runx1 increased (Table 1).…”

“…Among these, Runx1, which has close homology to a Drosophila protein, Runt, functions as a transcriptional activator or repressor for its target genes in concert with several specific coactivators or corepressors, depending on the context. 9 Importantly, presence of the NotchRunx pathway has been proposed in Drosophila embryonic hemocytogenesis 10 and zebrafish hematopoiesis during both developmental and postnatal periods. 11 Similarly reported has been transcriptional regulation by Notch of the Gata2 gene in mouse AGM hematopoiesis 8 and of the Gata homolog Serpent gene in Drosophila embryonic hemocytogenesis.…”

Crustacean hematopoiesis

“…The PSC provides niche signals to prohemocytes, which might stimulate renewal and block differentiation unless these cells are not needed in the circulatory system. PSC cells are determined early in Drosophila embryo development and have been characterized based on the expression of the Notch ligand Serrate (Lebestky et al, 2003), the transcription factors Collier/Knot (Col) and the homeotic Antennapedia gene (Morin-Poulard et al, 2013).…”