Mutations in the lysine demethylase 5 (KDM5) family of transcriptional regulators are associated with intellectual disability, yet little is known regarding the spatiotemporal requirements or neurodevelopmental contributions of KDM5 proteins. Utilizing the mushroom body (MB), a major learning and memory center within the Drosophila brain, we demonstrate that KDM5 is specifically required within ganglion mother cells and immature neurons for proper neurodevelopment and cognitive function. Within this cellular subpopulation, we identify a core network of KDM5-regulated genes that are critical modulators of neurodevelopment. Significantly, we find that a majority of these genes are direct targets of Prospero (Pros), a transcription factor with well-established roles in neurodevelopment in other neuronal contexts. We demonstrate that Pros is essential for MB development and functions downstream of KDM5 to regulate MB morphology. We therefore provide evidence for a KDM5-Pros axis that orchestrates a transcriptional program critical for proper axonal development and cognitive function.
bioRxiv Subject Collection: Neuroscience