Abstract
The embryonic ectoderm development (EED) is a core component of the polycomb-repressive complex 2 (PRC2) whose mutations are linked to neurodevelopmental abnormalities, intellectual disability, and neurodegeneration. Although EED has been extensively studied in neural stem cells and oligodendrocytes, its role in microglia is incompletely understood. Here, we show that microglial EED is essential for synaptic pruning during the postnatal stage of brain development. The absence of microglial EED at early postnatal stages resulted in reduced spines and impaired synapse density in the hippocampus at adulthood, accompanied by upregulated expression of phagocytosis-related genes in microglia. As a result, deletion of microglial Eed impaired hippocampus-dependent learning and memory in mice. These results suggest that microglial EED is critical for normal synaptic and cognitive functions during postnatal development.
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Data availability
The microglia RNA-seq data have been deposited in the Genome Sequence Archive in the National Genomics Data Center, Beijing Institute of Genomics, Chinese Academy of Sciences with accession number CRA006251.
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Acknowledgements
We appreciate the editors and five anonymous reviewers for the in-depth comments, suggestions, and corrections, which have greatly improved the paper. This work was supported by the National Key Research and Development Program of China Project (2018YFA0108001/2021YFA1101402), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16010300), the National Science Foundation of China (32170808), and the Open Project Program of State Key Laboratory of Stem Cell and Reproductive Biology.
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ZQT, CML, and YYW, conceived; ZQT, CML, and YT, supervised this study; YYW, ZQT, and CML, designed experiments; YYW, YSD, SKD, TWM, PPL, CL, RYL, BDH, XCH, HZD, and HCY, performed and analyzed experiments; SKD and YYW, performed bioinformatics analysis. YYW and ZQT, prepared figures and wrote the paper.
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Wang, YY., Deng, YS., Dai, SK. et al. Loss of microglial EED impairs synapse density, learning, and memory. Mol Psychiatry 27, 2999–3009 (2022). https://doi.org/10.1038/s41380-022-01576-w
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DOI: https://doi.org/10.1038/s41380-022-01576-w