A spatial atlas of the complement system uncovers unique expression patterns in postnatal brain development in mice
Recent studies have found non-immunological roles of the classical complement pathway (CP) in brain development and its involvement in neuropsychiatric and neurodegenerative diseases. However, multiple complement activation pathways exist beyond the CP, but their expression and function remain poorly understood in the brain. Using MERFISH, we constructed a comprehensive spatial transcriptomic atlas of the complement system in mouse brains from late embryonic stage to adulthood. Here we show that most complement genes are expressed locally with a remarkable degree of cellular, spatial, and temporal heterogeneity and that complement regulatory mechanisms are distinct from the periphery. Beyond confirming the known expression of the CP, our measurements reveal endogenous expression of the alternative pathway (AP), notably the AP activator Masp3 in immature brains. Masp3 deficiency alters molecular structure of the brain and causes working spatial memory defects, indicating a role of Masp3 in brain maturation, potentially via modulation of AP activity.
Authors
- Ajitanuj Rattan (ORCID: https://orcid.org/0000-0002-6564-2579)
- Minghe Ma (ORCID: https://orcid.org/0000-0002-4496-6240)
- Yilin Guan
- Barbara J. Caldarone (ORCID: https://orcid.org/0000-0003-3503-3104)
- Ludwig Geistlinger (ORCID: https://orcid.org/0000-0002-2495-5464)
- Brianna R. Watson (ORCID: https://orcid.org/0000-0001-6540-5330)
- Tyrone Lee (ORCID: https://orcid.org/0009-0008-7750-0448)
- Yingying Zhang (ORCID: https://orcid.org/0000-0002-3435-1330)
- Michael C. Carroll (ORCID: https://orcid.org/0000-0002-3213-4295)
- Jeffrey R. Moffitt (ORCID: https://orcid.org/0000-0002-3836-3101)
- Madhu Golla (ORCID: https://orcid.org/0000-0002-7729-2254)
- Takashi Miwa (ORCID: https://orcid.org/0000-0003-2670-6733)
- Smriti Chawla
- Wen‐Chao Song (ORCID: https://orcid.org/0009-0004-1740-843X)
- Finley B. Lord
Institutions
- Boston Children's Hospital (US)
- Boston Biomedical Research Institute (US)
- Harvard University (US)
- Boston VA Research Institute (US)
- Translational Therapeutics (United States) (US)
- University of Pennsylvania (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-02
- DOI
- https://doi.org/10.1038/s41467-025-66048-5
- Primary Topic
- Complement system in diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Institutes of Health
- National Institute of Mental Health
- National Institute of General Medical Sciences