Rett syndrome (RTT) is a severe childhood neurological disorder caused by mutations in the gene encoding Methyl-CpG-Binding Protein 2 (MeCP2). The molecular mechanisms underlying RTT are poorly understood, limiting the development of effective therapies. Loss of MeCP2 leads to widespread changes in gene expression, but it is unclear how these alterations give rise to RTT. This project aims to gain insights into the molecular basis of RTT through the identification of gene expression changes that are consistent across development and shared as a consequence of different RTT-causing MeCP2 mutations. Combining cell typespecific gene expression profiling and functional validation using in vivo CRISPR-based manipulations, these studies will define the molecular features of the RTT transcriptome, improving our understanding of RTT pathogenesis and revealing potentially novel targets for therapeutic development. In addition, this proposal constitutes a comprehensive graduate training plan that includes intellectual and technical research training, training in scientific communication and mentoring, coursework in bioinformatics and statistics, didactics in neuroscience, genetics, and epigenetics, as well as clinical training. Taken together, the studies outlined in this proposal will provide valuable information about the molecular basis of Rett syndrome and provide the applicant a strong training plan that will help him towards achieving his goal of becoming an independent investigator studying the pathogenic mechanisms underlying neurodevelopmental disorders.