ABSTRACT
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 will be to understand
how mutations in KDM5 contribute to neuronal and transcriptional outputs that influence cognition. Here, we will
utilize the genetically tractable Drosophila, which encodes a single ortholog of kdm5, to investigate neuronal
morphology, transcriptional outputs, and behavioral phenotypes of flies bearing patient-derived KDM5 missense
mutations. We have generated a set of ten fly strains, each of which harbors a conserved mutation in Drosophila
kdm5 that is analogous to an ID-associated allele. Preliminary data have demonstrated that RNAi-mediated
knockdown of kdm5 results in profound guidance and growth defects of the mushroom body (MB), a paired
neuropil-rich structure required for the acquisition, consolidation, and retrieval of long- and short-term memory.
Significantly, similar morphological MB defects are observed in flies bearing a mutation analogous to an ID-
causing missense mutation in an A/T rich interacting domain (ARID) previously implicated in KDM5 DNA binding.
Based on these and other data, our central hypothesis is that KDM5 is essential for MB development, and that
conserved ID-associated missense mutations that disrupt KDM5’s transcriptional activity lead to the
misexpression of genes required for MB morphology and cognitive function. This hypothesis will be tested in
three specific aims. The first will be to quantify the extent of MB defects in all kdm5 mutant strains harboring ID-
associated missense mutations at both gross and single-cell resolution. The second aim will define the gene
expression defects within MB neurons of kdm5 knockdown and ID mutant strains using combined genome-wide
transcriptome (RNA-seq) and binding (ChIP-seq) assays. Our third aim will quantify analogous cognitive and
behavioral phenotypes that are classically associated with ID. This work will thus be the first to utilize conserved
ID-causing KDM5 missense alleles to link ID-associated behavioral phenotypes with neuronal and transcriptional
regulatory programs, opening new avenues for the development of therapeutic strategies. Under the mentorship
and guidance of Drs. Julie Secombe and Nicholas Baker, I will be able to accomplish these goals while acquiring
new skills in developmental neuroscience and related fields. Additionally, I will gain valuable experience
presenting, networking, and preparing manuscripts, skills that are essential as I train to become an independent
investigator and physician-scientist in the neurosciences.
