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

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.

由于女性X染色体失活（X chromosome inactivation, XCI），显性X连锁疾病较为罕见。尽管随机XCI通常可使女性免受X连锁突变的影响，但雷特综合征（Rett syndrome, RTT）却是一种由杂合MECP2突变引发的女性神经发育障碍。在经历6至18个月的典型神经发育后，雷特综合征女童会出现发病机制尚不明确的退行性症状。本研究针对与雷特综合征造模相关的Mecp2e1突变小鼠模型的大脑皮层开展了纵向单细胞核RNA测序（single nuclear RNA sequencing, snRNA-seq），揭示了细胞类型、嵌合现象以及性别对疾病进展表型的转录调控效应。在所有细胞类型中，我们观察到存在性别二态性的差异表达基因（differentially expressed genes, DEGs）；在疾病进展全程中，雌雄个体仅共享9.2%的DEGs。雌性个体的DEGs在临床症状出现前即已出现，且随着病程推进在不同细胞类型中特异性富集于稳态基因通路，该表达特征与疾病表型以及人类雷特综合征皮层细胞转录组密切相关。在Mecp2e1突变雌性小鼠的疾病进展过程中，非细胞自主性效应呈现动态变化，提示表达野生型基因的细胞可恢复转录稳态。本研究结果加深了学界对雷特综合征疾病进展与治疗的认知。