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

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Dominant X-linked diseases are rare in females due to X chromosome inactivation (XCI).
• Rett syndrome (RTT) is a neurodevelopmental disorder in females caused by MECP2 mutations, characterized by regression after typical early development.
• The mechanisms underlying RTT progression remain poorly understood.

Purpose of the Study:

• To investigate the transcriptional changes associated with Rett syndrome progression in a mouse model.
• To understand the roles of cell type, mosaicism, and sex in RTT pathogenesis.
• To identify potential therapeutic targets for RTT.

Main Methods:

• 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 across different cell types and over disease progression.
• Differential gene expression analysis was conducted to compare mutant and wild-type mice, as well as males and females.

Main Results:

• Mutant females exhibited significantly more differentially expressed genes (DEGs) than mutant males (6x more).
• In females, DEGs appeared before symptom onset and were linked to homeostatic pathways, progressing dynamically over time.
• Non-cell-autonomous effects were observed, with wild-type-expressing cells contributing to the normalization of transcriptional homeostasis in mutant females.

Conclusions:

• Sex-specific transcriptional dysregulation and non-cell-autonomous effects are critical in RTT pathogenesis.
• The findings provide a deeper understanding of RTT progression and highlight the potential for therapeutic strategies targeting cellular interactions.
• This study advances knowledge on RTT and its complex molecular underpinnings.