The Drosophila intellectual disability-associated histone demethylase, KDM5, is required during early neurodevelopment for proper neuronal morphology

Intellectual disability (ID) disorders affect 2% of the population and are characterized by an IQ score lower than 70 with deficits in adaptive functioning. Mutations in over 400 genes contribute to the pathogenesis of ID disorders, with patients presenting with learning and memory impairments and often syndromic features such as epilepsy, anxiety, short stature, and aggressive tendencies. Our research focusses on the KDM5 family of transcriptional regulators, mutations in which account for 1-3% of inherited ID ranging from mild to severe. The molecular mechanisms by which KDM5 proteins impact neuronal function remain largely unknown, leaving patients without effective treatment strategies. Thus, the overarching goal of this project is to understand how KDM5 contributes to neuronal and transcriptional outputs that influence cognition, and how these processes are altered by kdm5 mutations associated with ID.

Here, we demonstrate that Drosophila, which possesses a single kdm5 ortholog, serves as a suitable and genetically tractable model to investigate the molecular and cellular defects associated with ID disorders. Combining analyses of a kdm5 null mutant with powerful genetic tools and behavioral paradigms, we are able to probe the neuronal requirements of KDM5 in vivo. Here, we present a role for KDM5 during early neurodevelopment in regulating neuronal morphology. We (1) demonstrate that KDM5 is required within immature neurons of the mushroom body, a brain structure critical for cognition, but not in mature cells, for proper mushroom body development, and (2) utilize Targeted DamID (TaDa) to identify differentially expressed KDM5 target genes within immature neurons of kdm5140 null mutants, allowing us to elucidate KDM5 transcriptional regulatory networks critical for neuronal development and cognitive function.