Gyrification of the cerebral cortex is essential for healthy brain development, and disruptions to this process lead to severe structural and functional abnormalities associated with long-term behavioural and psychiatric consequences. Basal radial glial cells (bRGC), residing in the expanded outer subventricular zone (oSVZ), are thought to drive gyrification. However, the transcriptional programs guiding this process remain poorly defined. We aimed to profile gene expression within the oSVZ of the developing ferret cortex, a species that displays postnatal gyrification, at two key stages of cortical folding, capturing its onset and progression. Discrete regions of the oSVZ were microdissected beneath the coronal gyrus and suprasylvian sulcus at the onset (P5, n = 5) and middle (P15, n = 5) of gyrification in the ferret. We performed RNA sequencing, differential expression analysis with gene ontology and pathway analyses with RT-qPCR validation of candidate genes. The results revealed spatially enriched gene sets associated with progenitor proliferation, self-renewal, and neurogenesis, as well as temporal transcriptional enrichment for axonogenesis and extracellular matrix regulation. RT-qPCR validated spatial and temporal expression differences, confirming consistent trends among some key folding-associated candidate genes. However, some genes (namely SOX9, AJAP1, and SEMA3D) showed inverse expression patterns compared to those detected by RNA-Seq and could not be considered validated. Together, these data define the molecular architecture of gyrification, providing a comprehensive transcriptional atlas of the oSVZ in the developing brain. Our findings advance understanding of how coordinated gene networks shape cortical folding, offering insights into the evolutional expansion of the mammalian brain.
M. Barresi, Alice Johnstone, Sebastian Quezada et al.· Brain Structure and Function· 0 citations
Microglia play dynamic roles in the developing brain and are central mediators of injury responses in perinatal brain injury. In mice, microglial gene regulatory and transcriptional programes reveal progression through early, pre-mature and mature stages. In contrast, microglial maturation has not been systematically characterised in the large-brained species most widely used to model human perinatal brain injury, particularly sheep and pigs. These large-animal models are indispensable as they share gyrencephaly, an expanded subplate, and clinically relevant physiology with the human infant brain. Here, we integrate established mouse and human frameworks of microglial maturation with a critical re-analysis of available sheep and pig datasets to assess whether rodent-derived insights into microglial development extend to large-animal models. Current sheep datasets lack sufficient resolution to infer maturation states, whereas pig data, although limited, reveal stage-dependent patterns consistent with late-gestation human development. This review also briefly considers emerging data on microglial development in non-human primates and the extent to which microglial gene expression programes appear conserved across species. Overall, microglial transitions are most dynamic during fetal and early postnatal life, underscoring the importance of developmentally aligned benchmarks for interpreting injury responses and informing microglia-targeted neuroprotective strategies. IMPACT: This article provides the first structured comparison of microglial maturation across human and mouse and uses these frameworks to benchmark large-brain animal models of perinatal brain injury, addressing a key translational gap. It shows that while existing sheep datasets lack sufficient resolution to define microglial maturation states, available pig data align closely with human late-gestation microglial development, supporting their use for developmental benchmarking. The work highlights that failure to account for microglial developmental stage risks misinterpretation of injury responses and underscores the need for developmentally aligned microglial markers in large-animal and non-human primate models to guide microglia-targeted neuroprotective strategies.
Isabelle K Shearer, Adrienne M. Antonson, Juliette van Steenwinckel et al.· Pediatric Research· 0 citations
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