Spatial dynamics of brain development and neuroinflammation
The ability to spatially map multiple layers of omics information across developmental timepoints enables exploration of the mechanisms driving brain development<sup>1</sup>, differentiation, arealization and disease-related alterations. Here we used spatial tri-omic sequencing, including spatial ATAC-RNA-protein sequencing and spatial CUT&Tag-RNA-protein sequencing, alongside multiplexed immunofluorescence imaging (co-detection by indexinng (CODEX)) to map dynamic spatial remodelling during brain development and neuroinflammation. We generated a spatiotemporal tri-omic atlas of the mouse brain from postnatal day 0 (P0) to P21 and compared corresponding regions with the human developing brain. In the cortex, we identified temporal persistence and spatial spreading of chromatin accessibility for a subset of layer-defining transcription factors. In the corpus callosum, we observed dynamic chromatin priming of myelin genes across subregions and identified a role for layer-specific projection neurons in coordinating axonogenesis and myelination. In a lysolecithin neuroinflammation mouse model, we detected molecular programs shared with developmental processes. Microglia exhibited both conserved and distinct programs for inflammation and resolution, with transient activation observed not only at the lesion core but also at distal locations. Overall, this study reveals common and differential mechanisms underlying brain development and neuroinflammation, providing a rich resource for investigating brain development, function and disease.
Authors
- Shuozhen Bao (ORCID: https://orcid.org/0000-0002-9301-9952)
- Rong Fan (ORCID: https://orcid.org/0000-0001-7805-8059)
- Arnold R. Kriegstein (ORCID: https://orcid.org/0000-0001-5742-2990)
- Per Uhlén (ORCID: https://orcid.org/0000-0003-1446-1062)
- Dejiang Wang (ORCID: https://orcid.org/0009-0003-8758-7966)
- Shigeaki Kanatani (ORCID: https://orcid.org/0000-0003-2226-4288)
- Petra Kukanja (ORCID: https://orcid.org/0000-0003-1228-5923)
- Nenad Šestan (ORCID: https://orcid.org/0000-0003-0966-9619)
- Yingxin Lin (ORCID: https://orcid.org/0000-0002-4299-7326)
- Mengyi Song (ORCID: https://orcid.org/0000-0002-6112-8521)
- Gonçalo Castelo‐Branco (ORCID: https://orcid.org/0000-0003-2247-9393)
- Leslie A. Kirby (ORCID: https://orcid.org/0000-0003-4467-2661)
- X Chen (ORCID: https://orcid.org/0009-0008-8812-9189)
- Yonglong Dang (ORCID: https://orcid.org/0000-0001-9705-5507)
- Cong Ma (ORCID: https://orcid.org/0000-0003-2532-0038)
- Hongyu Zhao (ORCID: https://orcid.org/0000-0003-1195-9607)
- Lijun Wang (ORCID: https://orcid.org/0000-0001-5222-4506)
- Li Wang (ORCID: https://orcid.org/0000-0001-9510-6294)
- Yang Liu (ORCID: https://orcid.org/0000-0003-1830-948X)
- Di Zhang (ORCID: https://orcid.org/0000-0001-8466-9868)
- Mei Zhong (ORCID: https://orcid.org/0000-0003-1230-0775)
- Shaohui Wang (ORCID: https://orcid.org/0000-0002-4203-4941)
- Wenqi Wang (ORCID: https://orcid.org/0000-0003-4053-5088)
- Hang Xu (ORCID: https://orcid.org/0000-0003-1100-6566)
- Jinmiao Chen (ORCID: https://orcid.org/0000-0001-7547-6423)
- Xing Lou
- Tony Jimenez-Beristain (ORCID: https://orcid.org/0009-0005-3756-3354)
- Fu Gao
Institutions
- Agency for Science, Technology and Research (SG)
- University of California, San Francisco (US)
- University of Michigan (US)
- Yale Cancer Center (US)
- Karolinska Institutet (SE)
- Yale University (US)
- Broad Center (US)
- Institute of Molecular and Cell Biology (SG)
Publication Details
- Journal
- Nature
- Published
- 2025-11-05
- DOI
- https://doi.org/10.1038/s41586-025-09663-y
- Citations
- 11
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 8.87