In an emerging paradigm, the peripheral nervous system (PNS) has been identified as a functional component of hematopoietic microenvironments and other stem cell niches. However, it remains largely unknown how the sensory nervous system and its inputs direct hematopoiesis or regulate blood cell responses, To address these questions at the molecular and cellular level, our team developed a simple model for PNS support and regulation of hematopoiesis, using the optically transparent larva of the genetically tractable model organism Drosophila melanogaster (Makhijani et al. Development 2011). The model shows parallels with vertebrate hematopoiesis in the bone marrow niche, and self-renewing tissue macrophages including the microglia of the brain (Makhijani and Brueckner, Fly 2012). Previously, we have shown that, during Drosophila larval development, blood cells (hemocytes) colonize 'hematopoietic pockets', where they accumulate in direct physical contact with segmentally repeated sensory PNS clusters, functionally rely on the PNS for their attraction and trophic survival, and are induced to proliferate in these microenvironments (Makhijani et al. Development 2011). At the molecular level, we identified PNS neuron-produced Activin as a key regulator of hemocyte adhesion and localization and identified N-cadherin (Ncad) as a potential mediator of hemocyte adhesion downstream of dSmad2. Further, we obtained evidence for an interface where environmental sensory stimuli, through activation of PNS neurons, are coupled with blood cell adhesion and localization. We hypothesize that in the Drosophila larval hematopoietic pockets, blood cell adhesion and other responses are controlled by signals emanating from the PNS microenvironment, which are constitutively produced and/or induced by neuronal activity and afferent inputs. The objective of this research is (1) to elucidate the role of Ncad or other adhesion molecules downstream of Activin/dSmad2 signaling in PNS- induced hemocyte adhesion, and (2) to dissect afferent stimulus PNS-hemocyte response circuits in larval hematopoiesis. To address these aims, we will use Drosophila genetics, in vivo and ex vivo analyses, live imaging, and a range of versatile neurobiology genetics tools. This research is innovative, because we established a simple Drosophila model for PNS support and regulation of hematopoiesis, and we will now utilize the system to understand the cellular and molecular principles of PNS-hematopoietic communication in the context of environmental sensory stimuli. This research is significant, because it is expected to provide precedence for specific afferent stimulus- PNS-blood cell response circuits, and identify new concepts of cellular, molecular and electrochemical communication between the PNS and cells of the hematopoietic system that govern blood cell development and homeostasis.
The proposed research is relevant to public health because it will address fundamental principles how the sensory nervous system and its afferent inputs direct hematopoiesis and regulate blood cell responses. In the big picture, this is significant for diseases caused by neuropathies and neural dysfunction, such as niche- induced hematologic, neuroinflammatory and neurodegenerative conditions that involve hematopoietic and immune cells. Use of a simple Drosophila model for peripheral nervous system (PNS)-regulated hematopoiesis will allow to dissect the cellular, molecular and electrochemical mechanisms of afferent stimulus-PNS-blood cell response circuits that may also be relevant for more complex, vertebrate hematopoietic microenvironments. Thus, the proposed research is relevant to the part of NIH's mission that pertains to developing fundamental knowledge that will help reduce the burdens of human disability.
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|Sopko, Richelle; Lin, You Bin; Makhijani, Kalpana et al. (2015) A systems-level interrogation identifies regulators of Drosophila blood cell number and survival. PLoS Genet 11:e1005056|
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|Gold, Katrina S; Brückner, Katja (2014) Drosophila as a model for the two myeloid blood cell systems in vertebrates. Exp Hematol 42:717-27|