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Spatial and temporal profiling of the complement system uncovered novel functions of the alternative

Apr 24, 2024

Mounting evidence implicated the classical complement pathway (CP) in normal brain development, and the pathogenesis of neuropsychiatric and neurodegenerative diseases. However the source and regulation of complement in the brain remain unclear. Using MERFISH, a spatial transcriptomic method with single-cell resolution, we established a developmental brain atlas of the complement system. We showed that the brain synthesizes essential building blocks of the complement system locally with remarkable cellular and spatial heterogeneity. We provided transcriptional evidence supporting the presence of the alternative pathway (AP), but lack of lectin pathway (LP) activity in postnatal brain development. Cell type, temporal and spatial expression patterns of genes involved indicate non-redundant functions of the CP and AP. In addition, deficiency in Masp3-driven AP resulted in developmental and cognitive defects, indicating essential functions of the AP, an observation that highlights the necessity to disentangle differential involvement of the three complement activation pathways in development and diseases.

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MERFISH is a massively multiplexed single-molecule imaging technology for spatially resolved transcriptomics capable of simultaneously measuring the copy number and spatial distribution of hundreds to tens of thousands of RNA species in individual cells.

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High multiplexing, high resolution in situ platform to combine single-cell and spatial genomics analysis powered by MERFISH technology.

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