Rabex-5 restricts Notch activity and maintains homeostasis in the Drosophila hematopoietic system.

摘要

Hematopoietic homeostasis requires the tight regulation of reservoirs of undifferentiated progenitors and the ability to control the replacement or expansion of blood cell lineages as necessary. A network of signaling pathways function to maintain hematopoietic homeostasis and disruption of signaling pathways is implicated in hematological malignancies such as leukemia. The spatiotemporal regulation and the coordination of pathways within the hematopoietic system, however, remain poorly understood. The work presented here uses Drosophila as a model to interrogate the regulation of the hematopoietic system by conserved signaling pathways.;Homozygous loss of Rabex-5 in Drosophila results in several hematopoietic abnormalities, including increased blood cell (hemocyte) concentration, altered hemocyte lineage distributions, increased size of the larval hematopoietic organ (the lymph gland), and the presence of lamellocytes and melanotic masses. Hematopoietic tissue-specific RNAi knockdown of Rabex-5 is sufficient to alter hemocyte lineage distribution, increase lymph gland size, and produce melanotic masses. Restoration of Rabex-5 in the hemocytes of Rabex-5 null larvae reduces larval lethality. Together, these data suggest that Rabex-5 is required within the hematopoietic system to maintain homeostasis. This work provides evidence that processes during embryonic and larval hematopoiesis have common and distinct requirements for Rabex-5.;Rabex-5 is known to restrict Ras activity and certain hematopoietic abnormalities resulting from Rabex-5 loss are dependent on excess Ras signaling. Many of the hematopoietic abnormalities are dependent on excess Notch activity independent of increased Ras signaling. Notch accumulates and its transcriptional activity increases in the lymph gland upon Rabex-5 knockdown. Rabex-5 is required in undifferentiated progenitors, but not in the hemocytes comprising a stem cell-like niche, to restrict Notch activity. This work demonstrates that Rabex-5 functions independently in the Drosophila hematopoietic system to restrict Ras and Notch activity.;Given the parallel functions of signaling pathways during Drosophila and mammalian hematopoiesis, regulation of the hematopoietic system by Rabex-5 has potential implications for human hematological diseases. Several hematopoietic abnormalities resulting from Rabex-5 loss including larval lethality, melanotic mass incidence, and increased lymph gland size are also dependent on hemocyte proliferation. Rabex-5 might serve to coordinate Ras and Notch activity to restrict blood cell proliferation and Rabex-5 loss might provide a relevant model for human leukemias.