UC Davis

Rett Syndrome (RTT) is a neurodevelopmental disorder primarily affecting females, caused by mutations in the MECP2 gene, which encodes the Methyl CpG binding protein (MeCP2). This dissertation explores various facets of MeCP2 function and its role in RTT, integrating findings from multiple studies to provide a comprehensive overview of the current understanding and research gaps.Chapter 1 reviews the known functions of MeCP2, emphasizing its role in transcriptional regulation and the impact of MECP2 mutations on RTT. The chapter summarizes key findings from human cell culture and rodent models, discusses controversies and gaps in the research, and highlights recent discoveries related to potential treatments and therapies. Chapter 2 investigates the effects of Mecp2e1 and MECP2 mutations on gene expression using longitudinal single-nucleus RNA sequencing (snRNA-seq 5’) in a Mecp2e1 mutant mouse model and human postmortem cortices. The study reveals significant sex differences in the number and nature of differentially expressed genes (DEGs), with mutant females showing more pronounced changes prior to symptom onset. These findings contribute to understanding the progression of RTT and the influence of non-cell-autonomous effects on transcriptional homeostasis. Chapter 3 examines the interaction between mutant Mecp2 and environmental factors, specifically persistent organic pollutants (POPs) like PCBs. By exposing wild-type and Mecp2e1 mutant dams to a PCB mixture, the study identifies overlaps in dysregulated genes and pathways between PCB exposure and Mecp2 mutations. This highlights the relevance of environmental factors in RTT pathology. Chapter 4 focuses on transcriptional dysregulation in the hypothalamus of Mecp2e1 mutant mice, using snRNA-seq 5’ to explore cell type-specific and sex-specific variations. The analysis reveals distinct disruptions in synaptic function, cellular metabolism, and neural development, with notable differences between the hypothalamus and cortex. This chapter provides insights into metabolic and neurodevelopmental changes associated with RTT and underscores the importance of considering both cellular and sex-specific factors. Together, these chapters offer a detailed examination of MeCP2’s role in RTT, integrating genetic, environmental, and cellular perspectives to advance the understanding of the disorder and inform future research directions.