Sex-specific single cell-level transcriptomic signatures of Rett syndrome disease progression

Dominant X-linked diseases are uncommon due to female X chromosome inactivation (XCI). While random XCI usually protects females against X-linked mutations, Rett syndrome (RTT) is a female neurodevelopmental disorder caused by heterozygous MECP2 mutation. After 6-18 months of typical neurodevelopment, RTT girls undergo poorly understood regression. We performed longitudinal snRNA-seq on cerebral cortex in a construct-relevant Mecp2e1 mutant mouse model of RTT, revealing transcriptional effects of cell type, mosaicism, and sex on progressive disease phenotypes. Across cell types, we observed sexually dimorphic differentially expressed genes (DEGs) with males and females sharing 9.2% DEGs through disease progression. Female DEGs emerged prior to symptoms, uniquely enriched for homeostatic gene pathways over time in distinct cell types, correlating with phenotypes and human RTT cortical cell transcriptomes. Non-cell-autonomous effects were dynamic across disease progression of Mecp2e1 mutant females, indicating wild-type-expressing cells normalizing transcriptional homeostasis. These results improve understanding of RTT progression and treatment.