A spatial atlas of the complement system uncovers unique expression patterns in postnatal brain development in mice

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Non-immunological roles of the classical complement pathway (CP) in brain development and disease are emerging.
• Expression and function of other complement pathways in the brain are largely unknown.

Purpose of the Study:

• To create a comprehensive spatial transcriptomic atlas of the complement system in the mouse brain.
• To investigate the expression patterns and functional roles of different complement pathways during brain development.

Main Methods:

• Multiplexed Error-Robust Fluorescence In Situ Hybridization (MERFISH) was employed.
• Spatial transcriptomics was used to map complement gene expression in mouse brains from embryonic to adult stages.

Main Results:

• Most complement genes exhibit localized expression with significant cellular, spatial, and temporal heterogeneity.
• Endogenous expression of the alternative pathway (AP), including the activator Masp3, was detected in immature brains.
• Masp3 deficiency resulted in altered brain molecular structure and impaired working spatial memory.

Conclusions:

• The brain possesses distinct complement regulatory mechanisms compared to the periphery.
• Masp3 plays a crucial role in brain maturation, potentially through modulating AP activity.
• These findings highlight novel roles for the complement system, particularly the AP, in neurodevelopment.