Size control of the Drosophila hematopoietic niche by bone morphogenetic protein signaling reveals parallels with mammals

Abstract

The Drosophila melanogaster larval hematopoietic organ, the lymph gland, is a model to study in vivo the function of the hematopoietic niche. A small cluster of cells in the lymph gland, the posterior signaling center (PSC), maintains the balance between hematopoietic progenitors (prohemocytes) and their differentiation into specialized blood cells (hemocytes). Here, we show that Decapentaplegic/bone morphogenetic protein (Dpp/BMP) signaling activity in PSC cells controls niche size. In the absence of BMP signaling, the number of PSC cells increases. Correlatively, no hemocytes differentiate. Controlling PSC size is, thus, essential for normal blood cell homeostasis. Activation of BMP signaling in the PSC requires expression of the Dally-like heparan-sulfate proteoglycan, under the control of the Collier/early B-cell factor (EBF) transcription factor. A Dpp > dpp autoregulatory loop maintains BMP signaling, which limits PSC cell proliferation by repressing the protooncogene dmyc. Dpp antagonizes activity of wingless (Wg)/ Wnt signaling, which positively regulates the number of PSC cells via the control of Dmyc expression. Together, our data show that Collier controls hemocyte homeostasis via coordinate regulation of PSC cell number and PSC signaling to prohemocytes. In mouse, EBF2, BMP, and Wnt signaling in osteoblasts is required for the proper number of niche and hematopoietic stem cells. Our findings bring insights to niche size control and draw parallels between Drosophila and mammalian hematopoiesis.TGF-β | hematopoiesis | myc

The EBF transcription factor Collier directly promotes Drosophila blood cell progenitor maintenance independently of the niche

“…Thus, we suggest that the PSC does not function as a niche required for blood cell progenitor maintenance. Several lines of evidence supporting the niche function of the PSC are based on ectopic or overexpression of various proteins in the PSC to alter its size and activity (11,13,15,17,21,29). These manipulations may not always reflect the real function of the PSC as they can cause sustained activation of abnormal programs that indirectly impinge on prohemocytes.…”

“…Its expression in the PSC is required for controlling PSC fate and cell number (10)(11)(12)15), whereas its expression in the prohemocytes prevents their premature differentiation. One Col mouse ortholog, Ebf2, has been shown to promote hematopoietic stem cell (HSC) maintenance by regulating the development of osteoblastic cells, which are part of the HSC niche (32).…”

“…It was thus proposed that the PSC provides a microenvironment that supports hematopoietic progenitor maintenance in the LG (10,11). In line with this model, increasing or decreasing PSC size/activity can, respectively, impede or promote hemocyte differentiation (11,(13)(14)(15)(16)(17)(18)(19). However, differentiated hemocytes are frequently observed close to the PSC, and it is unclear how progenitor fate is maintained in the posterior lobes, which are far apart and physically separated from the PSC.…”

La niche hématopoïétique de la drosophile

“…La voie de signalisation BMP (bone morphogenetic protein), conservée au cours de l'évolution, est impliquée [27,29]. L'étape suivante était de déterminer les conséquences du changement du nombre de cellules du PSC sur la différenciation des hémocytes ( Figure 4A) [21,27].…”

“…L'étape suivante était de déterminer les conséquences du changement du nombre de cellules du PSC sur la différenciation des hémocytes ( Figure 4A) [21,27].…”