The peripheral nervous system supports blood cell homing and survival in the Drosophila larva

Department of Cell and Tissue Biology, University of California-San Francisco, 35 Medical Center Way, San Francisco, CA 94143-0669, USA.
Development (Impact Factor: 6.46). 11/2011; 138(24):5379-91. DOI: 10.1242/dev.067322
Source: PubMed


Interactions of hematopoietic cells with their microenvironment control blood cell colonization, homing and hematopoiesis. Here, we introduce larval hematopoiesis as the first Drosophila model for hematopoietic colonization and the role of the peripheral nervous system (PNS) as a microenvironment in hematopoiesis. The Drosophila larval hematopoietic system is founded by differentiated hemocytes of the embryo, which colonize segmentally repeated epidermal-muscular pockets and proliferate in these locations. Importantly, we show that these resident hemocytes tightly colocalize with peripheral neurons and we demonstrate that larval hemocytes depend on the PNS as an attractive and trophic microenvironment. atonal (ato) mutant or genetically ablated larvae, which are deficient for subsets of peripheral neurons, show a progressive apoptotic decline in hemocytes and an incomplete resident hemocyte pattern, whereas supernumerary peripheral neurons induced by ectopic expression of the proneural gene scute (sc) misdirect hemocytes to these ectopic locations. This PNS-hematopoietic connection in Drosophila parallels the emerging role of the PNS in hematopoiesis and immune functions in vertebrates, and provides the basis for the systematic genetic dissection of the PNS-hematopoietic axis in the future.

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    • "Similar to vertebrates, blood cell differentiation in Drosophila is regulated in multiple hematopoietic environments, which include the head mesoderm of the embryo (Tepass et al., 1994; Lebestky et al., 2000; Milchanowski et al., 2004), the specialized, tissue-associated microenvironments of the larval periphery (e.g, body wall hematopoietic pockets) (Markus et al., 2009; Makhijani et al., 2011), and the larval lymph gland, an organ dedicated to the development of blood cells that normally contribute to the pupal and adult stages (Rizki, 1978; Shrestha and Gateff, 1982; Lanot et al., 2001; Jung et al., 2005). Understanding how blood cell development is regulated in the lymph gland is the primary goal underlying the work presented here. "
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    ABSTRACT: Blood progenitors within the lymph gland, a larval organ that supports hematopoiesis in Drosophila melanogaster, are maintained by integrating signals emanating from niche-like cells and those from differentiating blood cells. We term the signal from differentiating cells the ‘equilibrium signal’ in order to distinguish it from the ‘niche signal’. Earlier we showed that equilibrium signaling utilizes Pvr (the Drosophila PDGF/VEGF receptor), STAT92E, and adenosine deaminase-related growth factor A (ADGF-A) (Mondal et al., 2011). Little is known about how this signal initiates during hematopoietic development. To identify new genes involved in lymph gland blood progenitor maintenance, particularly those involved in equilibrium signaling, we performed a genetic screen that identified bip1 (bric à brac interacting protein 1) and Nucleoporin 98 (Nup98) as additional regulators of the equilibrium signal. We show that the products of these genes along with the Bip1-interacting protein RpS8 (Ribosomal protein S8) are required for the proper expression of Pvr. DOI:
    eLife Sciences 09/2014; 3:e03626. DOI:10.7554/eLife.03626 · 9.32 Impact Factor
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    • "Communication between the nervous system and the peripheral immune system is becoming more and more evident in mammals as well as in invertebrates, and it is now recognized that the immune and nervous systems rely on constant interaction to maintain homeostasis (Evans et al., 2010; Ransohoff and Engelhardt, 2012; An et al., 2014). For example, nonmyelinating Schwann cells associated with the autonomic innervation of bone marrow contribute to the maintenance of the hematopoietic stem cell pool in mice (Yamazaki et al., 2011), and the peripheral nervous system provides a microenvironment important for ''homing'' of hematopoietic cells and regulating their survival and development in Drosophila larvae (Makhijani et al., 2011). The studies presented in this article reveal a similarly intimate relationship between the immune and nervous systems in freshwater crayfish (Procambarus clarkii and Pacifastacus leniusculus), where the production of neurons continues throughout the organisms' lives (for review, see Beltz et al., 2011; Benton et al., 2013). "
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    ABSTRACT: Neurogenesis is an ongoing process in the brains of adult decapod crustaceans. However, the first-generation precursors that produce adult-born neurons, which reside in a neurogenic niche, are not self-renewing in crayfish and must be replenished. The source of these neuronal precursors is unknown. Here, we report that adult-born neurons in crayfish can be derived from hemocytes. Following adoptive transfer of 5-ethynyl-2'-deoxyuridine (EdU)-labeled hemocytes, labeled cells populate the neurogenic niche containing the first-generation neuronal precursors. Seven weeks after adoptive transfer, EdU-labeled cells are located in brain clusters 9 and 10 (where adult-born neurons differentiate) and express appropriate neurotransmitters. Moreover, the number of cells composing the neurogenic niche in crayfish is tightly correlated with total hemocyte counts (THCs) and can be manipulated by raising or lowering THC. These studies identify hemocytes as a source of adult-born neurons in crayfish and demonstrate that the immune system is a key contributor to adult neurogenesis.
    Developmental Cell 08/2014; 30(3):322-33. DOI:10.1016/j.devcel.2014.06.016 · 9.71 Impact Factor
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    • "The construction of in vivo reporters and hemocyte-specific GAL4 lines in recent years [15], [23]–[26] allowed a detailed anatomical and functional characterization of the hematopoietic compartments, and in particular the lymph gland [12], [13] and the sessile hematopoietic tissue [16], [17], [27], [28]. "
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    ABSTRACT: In recent years, Drosophila melanogaster has become an attractive model organism in which to study the structure and development of the cellular immune components. The emergence of immunological markers greatly accelerated the identification of the immune cells (hemocytes), while the creation of genetic reporter constructs allowed unique insight into the structural organization of hematopoietic tissues. However, investigation of the hemocyte compartments by the means of immunological markers requires dissection and fixation, which regularly disrupt the delicate structure and hamper the microanatomical characterization. Moreover, the investigation of transgenic reporters alone can be misleading as their expression often differs from the native expression pattern of their respective genes. We describe here a method that combines the reporter constructs and the immunological tools in live imaging, thereby allowing use of the array of available immunological markers while retaining the structural integrity of the hematopoietic compartments. The procedure allows the reversible immobilization of Drosophila larvae for high-resolution confocal imaging and the time-lapse video analysis of in vivo reporters. When combined with our antibody injection-based in situ immunostaining assay, the resulting double labeling of the hemocyte compartments can provide new information on the microanatomy and functional properties of the hematopoietic tissues in an intact state. Although this method was developed to study the immune system of Drosophila melanogaster, we anticipate that such a combination of genetic and immunological markers could become a versatile technique for in vivo studies in other biological systems too.
    PLoS ONE 06/2014; 9(6):e98191. DOI:10.1371/journal.pone.0098191 · 3.23 Impact Factor
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