Microglia expansion and clonality during development and disease

• Applicant: Dr. Tuan Leng Tay
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Developmental Neurobiology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2013 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 247929658

Microglia are macrophages exclusive to the CNS with multiple effector functions. In healthy brain, microglia perform housekeeping duties and respond rapidly to neuronal injury via the release of pro-inflammatory cytokines and phagocytotic activity. Microglia are a self-sustaining population that originate from yolk sac macrophages with a developmental signature distinct from haematopoietic stem cell-derived myeloid cells. The precise migratory and expansion events involved in the recruitment of yolk sac-derived macrophages to the CNS are largely unknown. First, I established in utero imaging of GFP-expressing macrophages in embryonic brain to understand the spatiotemporal aspects of these processes under in vivo conditions. My study proposes to provide a direct link between function and morphometry based on readouts from molecular markers and evolving macrophage or microglia morphology during the early stages of microglia development. Second, I generated novel inducible erythromyeloid progenitor- or microglia-specific multi-colour reporter mouse models and show clear evidence of clonal expansion of microglia in adult CNS of a neurodegeneration model. It is largely unexplored if different specialised microglia subclasses that exist within a micro-milieu of the brain parenchyma are derived from a single clonal origin or from different clones of microglial precursors that migrated from the yolk sac. Whether its local environment impacts the distinct function of each microglia subpopulation is also unknown. Furthermore, microglial clonal expansion and progression of inflammatory phenotypes during physiological state and in neuropathology are ill defined. For the first time, my transgenic lines make it possible to distinguish microglia clusters labelled in distinctive colours, for fate-mapping and systematic examination of these open questions during development and disease.

• DFG Programme: Research Grants