Thus, our platform can systematically uncover regulators of microglial states, enabling their functional characterization and therapeutic targeting. A disease-associated state characterized by osteopontin (SPP1) expression was selectively depleted by colony-stimulating factor-1 (CSF1R) inhibition. A screen with single-cell RNA sequencing as the readout revealed that these microglia adopt a spectrum of states mirroring those observed in human brains and identified regulators of these states. These screens uncovered genes controlling microglia survival, activation and phagocytosis, including neurodegeneration-associated genes. We established inducible CRISPR interference and activation in this system and conducted three screens targeting the ‘druggable genome’. We developed an efficient 8-day protocol for the generation of microglia-like cells based on the inducible expression of six transcription factors. Here, we present a screening platform to systematically elucidate functional consequences of genetic perturbations in human induced pluripotent stem cell-derived microglia. However, we lack a systematic understanding of the underlying mechanisms. Microglia are emerging as key drivers of neurological diseases.
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