Identification of factors regulating fate and function of microglia and macrophages in the CNS.

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The brain hosts a heterogeneous population of myeloid cells, including parenchymal microglia (MG), perivascular & meningeal macrophages and choroid plexus macrophages (M). In addition to functions during development myeloid cells are crucially involved in virtually all CNS diseases and myeloid dysfunction is thought to be causal for a group of diseases, called microgliopathies. Novel genetic and imaging methodologies will be employed by us to elucidate myeloid cell fate, diversity and function on single cell level. My proposal is pillared by three main approaches: First (Aim 1), we will challenge the classical few on the origin and fate of M. These cells are thought to be short lived and to derive, in contrast to yolk sac-derived MG , from circulating cells. Our prelimary data suggest a complete opposing view and suppose a different lineage. Second (Aim 2), kinetics and dynamics of MG & M networks during health and disease will be examined in vivo by using a new multicolour fluorescence fate mapping system that will provide new insights into cell homeostasis and renewal. Third (Aim 3), a distinct genetic signature in MG & M is thought to be the basis of their diverse biological functions. By applying massively parallel single cell RNAseq we will uncover their heterogeneity on single cell level in steady state. We expected that our results will fundamentally change our traditional view on brain myeloid cells.