Medical Microbiology and Immunology, School of Medicine, University of California, Davis, CA, USA.
Genome Center, University of California, Davis, CA, USA.
Commun Biol. 2024 Oct 10;7(1):1292. doi: 10.1038/s42003-024-06990-0.
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 a 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 sex differences in the number of differentially expressed genes (DEGs) with 6x more DEGs in mutant females than males. Unlike males, female DEGs emerged prior to symptoms, were enriched for homeostatic gene pathways in distinct cell types over time and correlated with disease phenotypes and human RTT cortical cell transcriptomes. Non-cell-autonomous effects were prominent and dynamic across disease progression of Mecp2e1 mutant females, indicating that wild-type-expressing cells normalize transcriptional homeostasis. These results advance our understanding of RTT progression and treatment.
X 连锁显性疾病较为罕见，这是由于女性 X 染色体失活（XCI）所致。虽然随机 XCI 通常能保护女性免受 X 连锁突变的影响，但雷特综合征（RTT）是一种由杂合 MECP2 突变引起的女性神经发育障碍。在典型的神经发育 6-18 个月后，RTT 女孩会经历一种尚未完全了解的退行性变化。我们在构建相关的 Mecp2e1 突变 RTT 小鼠模型的大脑皮层上进行了纵向 snRNA-seq 分析，揭示了细胞类型、镶嵌性和性别的转录效应对进行性疾病表型的影响。在所有细胞类型中，我们观察到性别差异与差异表达基因（DEG）的数量有关，突变雌性小鼠的 DEG 数量比雄性小鼠多 6 倍。与雄性小鼠不同，雌性小鼠的 DEG 出现在症状出现之前，随着时间的推移，不同细胞类型中与稳态基因途径相关的 DEG 更为丰富，并与疾病表型和人类 RTT 皮层细胞转录组相关。非细胞自主效应在 Mecp2e1 突变雌性小鼠的疾病进展过程中非常显著且具有动态性，表明表达野生型的细胞能使转录稳态正常化。这些结果提高了我们对 RTT 进展和治疗的认识。
