MECP2 impairs neuronal structure by regulating KIBRA

Using a Drosophila model of MECP2 gain-of-function, we identified memory associated KIBRA as a target of MECP2 in regulating dendritic growth. We found that expression of human MECP2 increased kibra expression in Drosophila, and targeted RNAi knockdown of kibra in identified neurons fully rescued dendritic defects as induced by MECP2 gain-of-function. Validation in mouse confirmed that Kibra is similarly regulated by Mecp2 in a mammalian system. We found that Mecp2 gain-of-function in cultured mouse cortical neurons caused dendritic impairments and increased Kibra levels. Accordingly, Mecp2 loss-of-function in vivo led to decreased Kibra levels in hippocampus, cortex, and cerebellum. Together, our results functionally link two neuronal genes of high interest in human health and disease and highlight the translational utility of the Drosophila model for understanding MECP2 function.