The research in the Brückner laboratory addresses fundamental questions in development, homeostasis, and malignant disease, studying paradigms in the invertebrate genetic model organism Drosophila melanogaster. Current research focuses on mechanisms of cell signaling, the role of the microenvironment, hematopoiesis, transdifferentiatrion, innate immunity, epithelial-mesenchymal transition, and organ development.
Nature and nurture- genetics and the environment in animal development, homeostasis, and malignant disease
Organismal research has traditionally focused on the role of genetic programs, and the contribution of physiological factors, such as nutrition and metabolism, and microbiota and pathogens. However, one of the outstanding questions in animal development, tissue homeostasis and malignant disease is how extrinsic sensory stimuli regulate these systems. The Brückner lab investigates the molecular mechanisms by which sensory inputs from the environment, through local neuronal connections, regulate development and disease. In addition, the lab studies more traditional drivers of development and disease including genetics and pathogen infections.
Regulation of hematopoiesis by sensory neurons and their environmental inputs
The Brückner lab studies the neuronal regulation of hematopoiesis, focusing on the hematopoietic sites (hematopoietic pockets) of the Drosophila larva that show parallels to vertebrate tissue macrophages (Makhijani et al. Development 2011; Makhijani et al. Fly 2012; Gold and Brückner, Seminars in Immunology 2015; Makhijani et al. Nature Communications 2017). In this system, blood cells (hemocytes) rely on sensory neuron microenvironments for their localization and trophic survival (Makhijani et al. Development 2011), and hemocyte proliferation is promoted by Activin-b produced by activated sensory neurons (Makhijani et al. Nature Communications 2017).
The lab currently examines mechanistic connections of environmental sensory stimuli, and the role of other neuron-produced factors on blood cell development and pathologies. A poorly understood aspect of hematopoiesis is transdifferentiation. Transdifferentiation generates specialized cell types independent of stem or progenitor cells.Focusing on the paradigm of transdifferentiation from macrophage-like plasmatocytes to crystal cells in the Drosophila larva (Corcoran et al. bioRxiv 2020), the Brückner lab found that this process is promoted by specific sensory neurons in the caudal sensory cones, and their activation by environmental oxygen sensing (Corcoran et al. bioRxiv 2020). We now systematically dissect the molecular mechanisms from oxygen sensing to blood cell transdifferentiation (collaboration with David Morton, OHSU, and Jiwon Shim, Hanyang University, Seoul).
Overall, our findings suggest similar principles of environmental regulation ofhematopoiesis in vertebrate systems where environmental sensors and blood cell populations coincide.
Signaling mechanisms of epithelial-mesenchymal transition
Epithelial-mesenchymal transition (EMT)is a transdifferentiation process of epithelial cells undergoing shape- and migratory changes, which is key to animal development and disease. A poorly understood group of EMT inducers are Bone Morphogenetic Proteins (BMPs), secreted ligands of the TGF-β family. BMP-induced EMT drives organ development, morphogenesis, and tumor metastasis, e.g. in heart development, thorax closure, and pancreatic cancer. However, the cell biological effects and cooperating signaling pathways of BMP-induced EMT are still under scrutiny. We investigate this question using a dual Drosophila model consisting of complementary cell-based and in vivo systems. For this purpose we established the novel Drosophila epithelial cell line, KaBrü1D, which mirrors Drosophila imaginal discs that undergo EMT and form the adult Drosophila thorax. Through RNAi screening, RNAseq and ChIPseq analyses in KaBrü1D cells, we identified new signaling mediators and pathways that cooperate with BMP signaling to induce EMT (collaboration with Jun Song, Univ. Illinois, and Julia Zeitlinger, Stowers Institute); findings are confirmed by Drosophila genetics in vivo.
Multi-tissue signaling relays in innate immunity
Innate immunity relies on humoral responses (e.g. expression of antimicrobial peptides (AMPs)) to protect the organism from infection and other pathological conditions. While core signaling pathways of the NFkB family and Jak/Stat signaling are well established in this context, it is far less understood how multiple organs and tissues communicate with each other to elicit powerful local humoral immune responses. We study this question of tissue communication in immunity using a simple Drosophila model. In adult Drosophila, the biggest reservoir of hemocytes surrounds the extensive respiratory epithelia (tracheal air sacs) of the thorax and head (Sanchez Bosch et al. Dev Cell 2019). The principal role of the adult blood cell system is to relay the trigger of bacterial infection and in turn elicit a humoral immune response in the respiratory epithelia and fat body (Sanchez Bosch et al. Dev Cell 2019). We dissect mechanisms of this relay including the coordination of multiple signaling pathways and consecutive signaling in multiple tissues, under conditions of bacterial infection and environmental challenges.