Supervisor: Dr Valérie Wittamer
The goal of our research is to provide novel insights into the ontogeny and functions of microglia, the resident-tissue macrophages of the central nervous system (CNS). Understanding these key aspects of microglia biology are of major importance since these cells serve multiple functions in physiology and disease and represent major targets for therapeutic intervention in a wide variety of neurological disorders, including neuroinflammation and neurodegeneration.
A major breakthrough in our understanding of microglia biology was the demonstration over the last few years that microglia exhibit specific differentiation and homeostatic features, which distinguish them from other populations of myeloid cells. Indeed, in contrast to blood monocytes which are constantly replenished from bone marrow-derived committed progenitors, microglia are maintained in the nervous tissue throughout life, independently from any bone marrow input. Because these findings have fundamental consequence on how to address microglia ontogeny and function for therapeutic purpose, they have opened new avenues for delineating the developmental program of microglia and its regulation. However, despite progress, the molecular mechanisms that control microglia specification and maintenance in the CNS are still poorly understood and remain to be determined.
Our group takes advantage of the unique attributes of the zebrafish model system to address microglia development in ways not possible in other vertebrates. Indeed, because the first steps of microglia ontogeny occur early during embryogenesis, transparent transgenic zebrafish embryos offer great opportunities to characterize these processes in a non invasive way. Through gene profiling, we have determined the molecular signature of zebrafish microglia, and have identified several candidate genes required for microglia development. In the proposed project, we will use state-of-the-art molecular, genetic and live imaging approaches to functionally characterize their specific contribution to microglia biology in vivo. The project will rely on targeted genome editing gene manipulation using the CRISPR/Cas9 technology to manipulate microglia gene functions in zebrafish and examine the subsequent effects on microglia biology through live imaging analyses on fluorescent transgenic embryos.
Insights into the molecular events that instruct microglial cell fates will ultimately advance current reprogramming protocols for generation of microglia-like cells in vitro for clinical use or to model disease in a dish.
Techniques:
Zebrafish breeding and embryo/larvae handling, in situ hybridization, molecular biology, transgenesis, microinjection, fluorescence microscopy, live imaging, flow cytometry….