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

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Rett syndrome (RTT) is a female neurodevelopmental disorder caused by heterozygous MECP2 mutations.
• X-chromosome inactivation (XCI) typically protects females from X-linked mutations, but RTT pathogenesis in females remains poorly understood.
• RTT girls exhibit regression after a period of typical development.

Approach:

• Longitudinal single-nucleus RNA sequencing (snRNA-seq) was performed on the cerebral cortex of a Mecp2e1 mutant mouse model of RTT.
• Transcriptional effects were analyzed based on cell type, mosaicism, and sex.
• Differential gene expression and pathway enrichment were investigated across disease progression.

Key Points:

• Mutant females exhibited 6x more differentially expressed genes (DEGs) than mutant males, with female DEGs appearing before symptom onset.
• Female DEGs were enriched for homeostatic gene pathways in specific cell types over time and correlated with disease phenotypes.
• Non-cell-autonomous effects were dynamic in mutant females, with wild-type-expressing cells potentially normalizing transcriptional homeostasis.

Conclusions:

• Sex-specific transcriptional changes are crucial in RTT pathogenesis.
• Understanding cell type-specific and dynamic gene expression patterns is key to RTT progression.
• These findings enhance comprehension of RTT and may inform therapeutic strategies.