The Peri group combines genetic approaches with quantitative imaging techniques to study how microglia shape neuronal connectivity by removing unwanted neurons and synapses.
Previous and current research
During brain development, neurons are generated in great excess and only those that make functional connections survive, while the majority is eliminated via apoptosis. Such huge numbers of dying cells pose a problem to the embryo, as leaking cell contents damages the surrounding environment. Therefore, the clearance of dying cells must be fast and efficient and is performed by a resident lineage of ‘professional’ phagocytes, the microglia. These cells patrol the entire vertebrate brain and sense the presence of apoptotic and damaged neurons. The coupling between the death of neurons and their phagocytosis by microglia is striking; every time we observe dead neurons we find them already inside the microglia. This remarkable correlation suggests a fast acting communication between the two cell types, such that microglia are forewarned of the coming problem and may even promote the controlled death of neurons during brain development. Despite the importance of microglia in several neuronal pathologies, the mechanism underlying their degradation of neurons remains elusive.
The zebrafish Danio rerio is an ideal model system to study complex cell-cell interactions in vivo. As the embryo is optically transparent, the role of molecular regulators identified in large-scale forward and reverse genetic screens can be studied in vivo. Moreover, a key advantage of the system is that zebrafish microglia are extremely large, dynamic cells that form a non-overlapping network within the small transparent fish brain. Labelling microglia, neurons and organelles of the microglial phagocytotic pathway simultaneously in the living zebrafish embryos allows us to image, for the first time, the entire microglial population in order to study the interaction between neurons and microglia.
Future projects and goals
How microglia collectively ensure that the entire brain is surveyed and how they react to damage with high precision is still entirely unknown. Recent findings suggest that diffusible molecules such as lipids and nucleotides could attract microglia in response to neuronal apoptosis and injury, respectively. While these molecules can trigger dynamic changes in microglia motility in vitro, elucidating how their activity is controlled within the intact brain, both in space and time, remains the most important challenge in understanding this fascinating biological problem. We aim to further exploit the massive imaging potential of the transparent zebrafish embryo for studying microglial biology in vivo. By combining forward and reverse genetic approaches with quantitative imaging technology, we will directly address the mechanisms underlying the attraction of microglia towards apoptotic, sick and injured neurons. By applying cutting-edge microscopy technology, such as the SPIM/DSLM (Selective Plane Illumination Microscopy), we will image all interactions between neurons and microglia and derive from this time-lapse analysis real quantitative data in a spatiotemporal manner.