Intellectual disabilities are the most common type of developmental disorder, affecting approximately 8 million Americans and an estimated 1% of the world population. These disorders are defined by significant limitations in intellectual functioning and adaptive behaviors often associated with low IQ (?70). In many cases the etiology of intellectual disability is complex or unknown, but some cases of the disorder are monogenic and thus provide insight into cellular and molecular mechanisms underlying brain dysfunction. We have found that loss of the human ZC3H14 gene, which encodes an RNA-binding protein, leads to an inherited form of autosomal recessive intellectual disability. To gain insight into ZC3H14 role's in the brain, we created a model of ZC3H14 loss by deleting it's homolog, dNab2, in the fruit fly Drosophila melanogaster, which is a well- established system to model human neurological disease. Our studies have revealed that loss of dNab2 within neurons impairs locomotor behavior and short-term memory, and simultaneously alters patterns of axon guidance within the mushroom bodies, twin neuropil structures involved in fly learning and memory. Intriguingly, these phenotypes are accompanied by an underlying molecular effect on levels of m6A (methylation of adenosine at position-N6) RNA modification, which is an abundant covalent modification that is implicated in control of RNA splicing, stability, and translation. m6A levels are substantially elevated in the dNab2 mutant neuronal transcriptome, suggesting that dNab2 modulates neuronal gene expression in part by affecting m6A modification of individual RNAs. In support of this hypothesis, I have gathered evidence that the m6A methlytransferase Ime4 is genetically required for phenotypic effects of dNab2 alleles in retinal neurons. Thus, I hypothesize that dNab2 regulates brain function by modulating Ime4-dependent m6A modification of specific neuronal RNAs. This hypothesis will be tested in three independent but complementary Aims in which I will: 1) Determine whether Ime4 is required for mushroom body development in a manner similar to dNab2; 2) Test for genetic interactions between dNab2 and Ime4 in neurodevelopment and behavior and 3) Map the distribution of m6A modification in neuronal RNAs in the presence and absence of dNab2. Our long-term goal is to use our established Drosophila model to provide key molecular insights into how dNab2 affects neuronal gene expression in the fly brain.
Intellectual disability, also known as mental retardation, is a common developmental disorder affecting roughly 1% of the world population. We study an early-onset form of intellectual disability resulting from the loss of a single factor, ZC3H14, in a fruit fly model. The long-term goal of this project is to understand how changes in ZC3H14 can lead to intellectual disability and to thus provide improved understanding of this early-onset neurodevelopmental disorder and other mental health diseases.
