Early transcriptional signatures of MeCP2 positive and negative cells in Rett syndrome

作者：Yan Li, Ashley G. Anderson, Guanxiao Qi, Sih‐Rong Wu, Jean‐Pierre Revelli, Zhandong Liu, Huda Y. Zoghbi · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2025 · DOI：10.1101/2025.06.26.661761 · 被引用次数：5 · 研究领域：Genetics and Neurodevelopmental Disorders、Autism Spectrum Disorder Research、Family and Disability Support Research

Abstract Rett syndrome (RTT) is an X-linked neurological disorder caused by MECP2 mutations. Like other X-linked disorders, RTT patients have sex-specific differences in clinical presentation due to distinct cellular environments, where females have ∼50% of cells expressing either a mutant or wild-type copy of MECP2 (mosaic) and males have 100% of cells expressing a mutant MECP2 (non-mosaic). Typical RTT females have a short window of normal early development until ∼6-18 months, followed by regression and progressive decline, whereas neonatal encephalopathy is more likely in RTT males. How these sex-specific differences in cellular context contribute molecularly to RTT pathogenesis, particularly in the presymptomatic stages of RTT females, remains poorly understood. Here, we profiled the hippocampal transcriptomes of female ( Mecp2 +/- ) and male ( Mecp2 -/y ) RTT mice at early timepoints using both bulk and single-nucleus RNA-seq, including sorted MeCP2 positive (MeCP2+) and MeCP2 negative (MeCP2-) neurons in female mice. We identified a core disease signature consisting of 12 genes consistently dysregulated only in MeCP2-cells across RTT models. Moreover, we uncovered non-cell-autonomous effects exclusively in female MeCP2+ excitatory neurons, but not inhibitory neurons, suggesting excitatory circuits are more vulnerable early in the mosaic RTT environment. The single-nuclei data also revealed that a previously underappreciated MeCP2-interneuron subtype had the most transcr...