Mutations in the lysine demethylase 5 (KDM5) family of transcriptional regulators are found in patients with intellectual disabilities (ID) that show cognitive impairment ranging from mild (IQ 50-70) to severe (IQ < 30). However, the molecular mechanisms by which KDM5 proteins impact neuronal development and function remain unknown, leaving a large knowledge gap and preventing the identification of potential treatments for affected patients. Thus, the long-term goal of our research is to define at the molecular level how KDM5 regulates gene expression patterns necessary for neuronal development and function. We will achieve this using Drosophila because it is an established model organism used to define the molecular basis of human neurodevelopmental disorders. Studies described here use a powerful combination of genetic tools, cell biological analyses and cognitive behavioral assays to dissect KDM5?s gene regulatory activities in neuronal cells at distinct stages of development. In addition to classical loss of function analyses utilizing a newly generated kdm5 null allele and cell type specific inducible RNAi-mediated knockdown assays, we have generated a set of eight fly strains, each of which harbors a mutation in Drosophila kdm5 analogous to a human ID allele. This approach is possible because all disease-associated mutations occur in evolutionarily conserved amino acids. Data generated using these tools lead us to propose the central hypothesis that KDM5 regulates the expression of genes essential for neuronal development and function, and that this is affected by missense mutations associated with intellectual disability. This hypothesis will be tested in three specific aims.
The first aim addresses the role of KDM5 in adult brain function by defining the mechanism by which KDM5 activates ribosomal protein (Rp) genes, as de novo translation has an evolutionarily conserved role in learning and memory.
The second aim focusses on the role of KDM5 during development by determining the mechanism by which KDM5 functions in larval neuronal stem cells (neuroblasts) to facilitate the subsequent growth and guidance of the neurons required for learning and memory.
The third aim defines the temporal and spatial requirements of KDM5 for learning and memory. This work is significant because we will define new mechanisms of gene regulation by KDM5 that are critical for neuronal development and activity in addition to providing insight into the underlying causes of neurodevelopmental disorders.
Intellectual disability adversely affects the quality of life of both the affected individual and their caregivers. By understanding the molecular basis of intellectual disability caused by mutations in the transcriptional regulator KDM5, we will provide much needed information regarding the etiology of cognitive impairment. This in turn is expected to highlight potential targets for developing therapies for patients.
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