Abstract
ABSTRACTHematopoietic homeostasis requires the maintenance of a reservoir of undifferentiated blood cell progenitors and the ability to replace or expand differentiated blood cell lineages when necessary. Multiple signaling pathways function in these processes, but how their spatiotemporal control is established and their activity is coordinated in the context of the entire hematopoietic network are still poorly understood. We report here that loss of the gene Rabex-5 in Drosophila causes several hematopoietic abnormalities, including blood cell (hemocyte) overproliferation, increased size of the hematopoietic organ (the lymph gland), lamellocyte differentiation and melanotic mass formation. Hemocyte-specific Rabex-5 knockdown was sufficient to increase hemocyte populations, increase lymph gland size and induce melanotic masses. Rabex-5 negatively regulates Ras, and we show that Ras activity is responsible for specific Rabex-5 hematopoietic phenotypes. Surprisingly, Ras-independent Notch protein accumulation and transcriptional activity in the lymph gland underlie multiple distinct hematopoietic phenotypes of Rabex-5 loss. Thus, Rabex-5 plays an important role in Drosophila hematopoiesis and might serve as an axis coordinating Ras and Notch signaling in the lymph gland.
Highlights
Drosophila melanogaster has served as a genetic model for studying signaling mechanisms controlling hematopoietic processes (Dearolf, 1998; Evans et al, 2003; Jung et al, 2005; Martinez-Agosto et al, 2007; Crozatier and Vincent, 2011) for several decades
Rabex-5 is required in Drosophila blood cells to prevent melanotic masses We previously reported melanotic mass formation (Fig. 1A), and larval and pupal lethality in Drosophila that lack the neoplastic tumor suppressor Rabex-5 (Yan et al, 2010)
In the absence of parasitization, melanotic masses are often associated with abnormalities in the hematopoietic system, including autoimmune-like responses to self-tissue and dysregulation of proliferation leading to excess hemocyte numbers (Watson et al, 1994; Asha et al, 2003; Zettervall et al, 2004; Minakhina and Steward, 2006)
Summary
Drosophila melanogaster has served as a genetic model for studying signaling mechanisms controlling hematopoietic processes (Dearolf, 1998; Evans et al, 2003; Jung et al, 2005; Martinez-Agosto et al, 2007; Crozatier and Vincent, 2011) for several decades. Drosophila blood cells, collectively known as hemocytes, arise from a common, multipotent progenitor population called prohemocytes in two waves of hematopoiesis: first during. Lamellocytes, a large and adherent cell type, only differentiate in the larval stage in response to large pathogens, wounding and tissue overgrowth. They do not appear in unchallenged, wild-type larvae (Rizki and Rizki, 1992; Lanot et al, 2001; Sorrentino et al, 2002; Markus et al, 2005; PastorPareja et al, 2008)
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