Extracellular matrix-modulated FGF signaling in Drosophila blood progenitors regulates their differentiation via a ras/ETS/FOG pathway and TORC1 function
. Julian A. Martinez-Agosto, Michelle Dragojlovic-Munther. Department of Human Genetics, University of California Los Angeles, Los Angeles, CA.

   Maintenance of hematopoietic progenitors ensures a continuous supply of blood cells during the lifespan of an organism. In particular, these progenitors are required for the cellular immune response against foreign pathogens and tissue injury. A large pool of undifferentiated blood progenitors are maintained in the Drosophila hematopoietic organ, the larval lymph gland (LG), by a complex network of signaling pathways that are mediated by niche-, progenitor-, or differentiated hemocyte-derived signals. We have examined the function of the Drosophila Fibroblast Growth Factor receptor (FGFR), Heartless (Htl), a critical regulator of early LG progenitor specification in the late embryo, during later hematopoiesis. Activation of Htl signaling in hemocyte progenitors by its two ligands, Pyramus (Pyr) and Thisbe (Ths), is both required and sufficient to induce progenitor differentiation and formation of the plasmatocyte-rich LG cortical zone. We identify two transcriptional regulators that function downstream of Htl signaling in LG progenitors, the ETS protein, Pointed, and the Friend-of-GATA (FOG) protein, U-Shaped, which are required downstream of Ras signaling for this Htl-induced differentiation response. Furthermore, cross-talk of FGFR and Target of Rapamycin (TOR) signaling in hemocyte progenitors is required for lamellocyte differentiation downstream of Ths-mediated Htl activation. Finally, we identify the Drosophila heparan sulfate proteoglycan (HSPG), Trol, as a crucial negative regulator of FGF signaling in the LG. Trol knockdown promotes precocious progenitor differentiation, and this phenotype is rescued by downregulation of Pyr or Ths, demonstrating the interaction between Trol and FGF ligands. These findings demonstrate that sequestration of differentiation signals by the extracellular matrix is a unique mechanism employed in blood progenitor maintenance that is of potential relevance to the cellular immune response and many other stem cell niches.