Tsc1 and Tsc2 maintain hematopoietic homeostasis through multiple signaling pathways in Drosophila

The lymph gland is the main hematopoietic tissue in Drosophila larvae, regulated by multiple signaling pathways and serving as a valuable genetic model for studying hematopoiesis. Investigating hematopoietic mechanisms in Drosophila can provide valuable insights into the pathogenesis of human hematopoietic malignancies. Tsc1 and Tsc2 are tumor suppressor genes mutated in tuberous sclerosis complex, a tumor syndrome. The protein complexes formed by their gene products have attracted considerable interest in the field of signaling research. However, their roles in maintaining hematopoietic homeostasis remain unclear. In this study, we found that knockdown of Tsc1 or Tsc2 in the intermediate zone and cortical zone leads to increased proliferation and differentiation of hemocytes, accompanied by disruption of progenitor cell maintenance in the medullary zone. Aberrant differentiation of lamellocytes was also observed, along with a marked increase in both the size and number of circulating hemocytes. Furthermore, Tsc1 or Tsc2 knockdown elevated levels of cell death in both the lymph gland and circulating hemocytes. Our findings suggest that Tsc1 and Tsc2 play multifaceted roles in regulating hematopoietic homeostasis through the TOR and Notch signaling pathways. Additionally, Tsc2 contributes to hematopoietic regulation via the JNK pathway and is also involved in apoptosis regulation. In conclusion, our findings revealed that Tsc1 and Tsc2 function within the intermediate zone and cortical zone of the lymph gland to maintain hematopoietic homeostasis through multiple signaling pathways.