The developing mouse brain is a construction site where millions of neurons migrate to final positions, guided by molecular signals that act like cellular GPS. But when a mother’s immune system flares or her gut bacteria get wiped out, that guidance system malfunctions, and it malfunctions differently in male versus female embryos. New spatial mapping reveals the exact locations where these sex-specific disruptions occur, pointing to a single pathway that may explain why neurodevelopmental conditions skew heavily male.
Brian Kalish’s team at Boston Children’s Hospital used MERFISH spatial transcriptomics to visualize 500 immune-related genes in embryonic mouse brains during mid and late gestation. The technique captures RNA molecules in their original tissue locations, creating color-coded maps of the cortical plate where maturing neurons stack atop the ventricular zone’s progenitor cells. When they compared healthy embryos to those exposed to maternal immune activation or antibiotic-induced microbiome depletion, a pattern emerged: male brains reorganized their immune landscape more dramatically than female brains.
The CXCL12/CXCR7 chemokine pathway proved especially sensitive. This molecular network guides neural progenitor cells through differentiation into functioning neurons. Male progenitor cells exposed to CXCL12 differentiated prematurely, altering cortical layer thickness. Female cells barely responded to the same signal.
Microglia Crowd Differently By Sex
After maternal microbiome depletion, microglia—the brain’s resident immune cells—clustered more densely around migrating neurons in male embryos. Female embryos showed no comparable shift. Kalish integrated single-cell RNA sequencing with the spatial data to sharpen cell-type context, confirming that male brains appear primed at baseline to react more intensely to environmental disruptions.
This isn’t about inflammation in any simple sense. The fetal brain has its own immune signaling patterns that are developmentally regulated and spatially organized. Maternal stressors don’t “inflame” the brain so much as retune its molecular geography.
“As a neonatologist, this work adds to our understanding early-life environmental factors that may impact neurodevelopmental potential and lends insights for potential interventions,” Brian Kalish explains.
A Single Pathway Links Multiple Stressors
Both maternal immune activation and microbiome depletion converged on the same CXCL12/CXCR7 mechanism in male embryos. Whether the disruption came from immune signals or gut bacteria loss, the downstream effects looked similar: premature neural differentiation, altered cortical architecture, shifted microglia distribution. Finding a common pathway across distinct stressors offers a concrete target for protective strategies.
The epidemiological patterns fit. Autism, ADHD, and related conditions occur more frequently in males. If male fetal brains are more reactive to maternal immune and gut signals during critical windows, interventions that stabilize those signals during pregnancy could reduce risk. Kalish frames the atlas as a neonatology tool—a way to see which molecular switches get flipped early, when buffering might still work.
The MERFISH panel was limited to immune ligands and receptors, leaving other molecular pathways unmapped for now. But the approach makes visible what epidemiology could only infer: the spatial architecture of how maternal health programs fetal brain development, one chemokine gradient at a time.
Nature Neuroscience: 10.1038/s41593-025-02162-3
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