Dual role for Insulin/TOR signaling in the control of hematopoietic progenitor maintenance in Drosophila

Abstract

The interconnected Insulin/IGF signaling (IlS) and Target of Rapamycin (TOR) signaling pathways constitute the main branches of the nutrient-sensing system that couples growth to nutritional conditions in Drosophila. Here, we addressed the influence of these pathways and of diet restriction on the balance between the maintenance of multipotent hematopoietic progenitors and their differentiation in the Drosophila lymph gland. In this larval hematopoietic organ, a pool of stem-like progenitor blood cells (prohemocytes) is kept undifferentiated in response to signaling from a specialized group of cells forming the posterior signaling center (PSC), which serves as a stem cell niche. We show that, reminiscent of the situation in human, loss of the negative regulator of IIS Pten results in lymph gland hyperplasia, aberrant blood cell differentiation and hematopoietic progenitor exhaustion. Using site-directed loss- and gain-of-function analysis, we demonstrate that components of the IIS/TOR pathways control lymph gland homeostasis at two levels. First, they cell-autonomously regulate the size and activity of the hematopoietic niche. Second, they are required within the prohemocytes to control their growth and maintenance. Moreover, we show that diet restriction or genetic alteration mimicking amino acid deprivation triggers progenitor cell differentiation. Hence, our study highlights the role of the IIS/TOR pathways in orchestrating hematopoietic progenitor fate and links blood cell fate to nutritional status.

ARF1–GTP regulates Asrij to provide endocytic control of Drosophila blood cell homeostasis

“…S9). PSC-specific overexpression of Pten, an inhibitor of insulin signaling causes a reduced niche and reduced differentiation (22). We observed that overexpression of ARF1 alone in the niche (PCol85Gal4GFP/UASarf1) does not affect niche cell number (Fig.…”

“…For example, sumoylation defective mutants like Ubc9 show posterior lymph gland tissue overgrowth (31). Pten mutants also display secondary lymph gland lobe overgrowth with numerous proliferating cells (22). Even in asrij-depleted posterior lobes stemness is lost and cells differentiate (6).…”

“…Recently insulin signaling was shown to control prohemocyte maintenance (22) and an ARF-GEF Steppke is speculated to regulate the insulin signaling pathway by activating ARF (23), thereby completing the cycle of ARF activation and inactivation. Steppke is thought to act upstream of PI3K (24).…”

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

“…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.…”

Age Regulates Drosophila Ovarian Germline Stem Cells via Insulin-Dependent and Independent Mechanisms

“…In Drosophila, neural-producing Dilps cell-autonomously regulate male GSC division at the G2 phase, as well as GSC and hematopoietic progenitor maintenance [17][18][19]. They also non-cell autonomously control midgut intestinal stem cell proliferation [20].…”