Affiliations: 1) Albert Einstein College of Medicine; 2) University of Tasmania
Keywords: b. neural disorder; a. axon guidance
Intellectual disability (ID) disorders affect up to 2% of the population and are characterized by an IQ score less than 70 with deficits in adaptive functioning. Our research focuses on the KDM5 family of transcriptional regulators (KDM5A, KDM5B, KDM5C, and KDM5D), mutations in which account for 1-3% of inherited ID ranging from mild to severe. Although recent advances in comparative genomic hybridization and whole exome sequencing have revealed approximately 70 unique genetic variants in KDM5C segregating in families with inherited ID, the molecular mechanisms by which this family of proteins impacts neuronal function remain largely unknown, leaving patients without effective treatment strategies.
Here, we utilize the Drosophila Mushroom body (MB), a major learning and memory center within the fly brain, to demonstrate that Drosophila KDM5 is specifically required within ganglion mother cells (GMCs) and immature neurons for proper neurodevelopment. Utilizing Targeted DamID (TaDa), we identify a core network of KDM5-regulated genes within GMCs and immature neurons 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 neuronal growth and guidance. We further demonstrate that pros genetically interacts with kdm5 to orchestrate a transcriptional program critical for proper MB development.
To better understand the molecular mechanisms through which KDM5 functions to regulate MB development, we generated a library of fly strains each bearing a conserved ID patient-derived kdm5 missense mutation. We demonstrate that a subset of these strains presents with MB structural defects and deficits to long-term memory, as assessed via appetitive olfactory conditioning assays. Interestingly, fly strains bearing patient mutations that disrupt KDM5’s histone demethylase activity do not present with MB morphological defects, yet have impaired learning and memory. These data suggest that KDM5 may function through demethylase-independent mechanisms to regulate MB development, independent of its effect on cognitive function. This is significant, as the prevailing model linking KDM5 dysfunction to ID assumes that altered demethylase activity of KDM5 is largely responsible for such deficits. We are currently investigating how KDM5 may utilize specific protein domains in coordination with Pros to guide neuronal development.