MECP2-mutant marmosets exhibit primate-specific phenotypes of Rett syndrome

We used genome editing to generate MECP2-knockout marmosets and establish a new primate model for Rett syndrome (RTT), a neurodevelopmental disorder. MRI analysis of this marmoset model revealed diminished cortico-cortical connections, particularly those originating in the prefrontal cortex. Detailed histological analysis revealed reduced dendritic arborization and synaptic density, particularly in the upper layers of the cerebral cortex. Cortical layer II/III excitatory neurons appeared to be immature based on single-nucleus RNA sequencing and spatial transcriptomics, while PVALB-positive interneurons exhibited upregulation of neuronal maturation-related transcripts. Moreover, the neurodevelopmental disease gene GABAB receptor 2 (GABBR2) emerged as a conserved downstream target of MECP2, illuminating a cellular cascade that could be targeted in preclinical and therapeutic drug development. Many of the gene expression changes observed in the marmoset model are common in RTT patients, thereby highlighting molecular links from cell type-specific phenotypes in the marmoset model to the RTT clinical presentation.