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Molecular Cartography of the Human and Mouse Down Syndrome Brain [MERFISH]

ABSTRACT: Given the importance of linking human and model system pathobiology, we also performed highly multiplexed RNA in situ spatial transcriptomics on a well-established trisomic mouse model (Ts65Dn) to study the cellular landscape of the trisomic brain during early life and aging. We profiled the spatial transcriptome of > 240,000 cells in the mouse brain and identified trisomy-associated gene expression patterns in the molecular control of neurogenesis, gliogenesis, and myelination. Multiplexed error-robust fluorescence in situ hybridization (MERFISH) was performed on postnatal day 0 (P0) and 6 month (6mo) euploid and trisomic (Ts65Dn) mice (n=3 per condition). Coronal sections of the entire brain were used for analysis.

ORGANISM(S): synthetic construct Mus musculus

PROVIDER: GSE280177 | GEO | 2025/07/11

REPOSITORIES: GEO

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Project description:In mammalian brains, millions to billions of cells form complex interaction networks to enable a wide range of functions. The enormous diversity and intricate organization of cells have impeded our understanding of the molecular and cellular basis of brain function. Recent advances in spatially resolved single-cell transcriptomics have enabled systematic mapping of the spatial organization of molecularly defined cell types in complex tissues. However, these approaches have only been applied to a few brain regions and a comprehensive cell atlas of the whole brain is still missing. Here, we imaged a panel of >1,100 genes in ~10 million cells across the entire adult mouse brain using multiplexed error-robust fluorescence in situ hybridization (MERFISH) and performed spatially resolved, single-cell expression profiling at the whole-transcriptome scale by integrating MERFISH and single-cell RNA-sequencing (scRNA-seq) data. Using this approach, we generated a comprehensive cell atlas of >5,000 transcriptionally distinct cell clusters, belonging to >300 major cell types, in the whole mouse brain with high molecular and spatial resolution. Registration of this atlas to the mouse brain common coordinate framework (CCF) allowed systematic quantifications of the cell-type composition and organization in individual brain regions. We further identified spatial modules characterized by distinct cell-type compositions and spatial gradients featuring gradual changes of cells. Finally, this high-resolution spatial map of cells, each with a transcriptome-wide expression profile, allowed us to infer cell-type-specific interactions between several hundred cell-type pairs and predict molecular (ligand-receptor) basis and functional implications of these cell-cell interactions. These results provide rich insights into the molecular and cellular architecture of the brain and a foundation for future functional investigations of neural circuits and their dysfunction in diseases.

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Molecular Cartography of the Human and Mouse Down Syndrome Brain [MERFISH]

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