View Program - 63rd Annual Drosophila Research Conference

Inherited forms of intellectual disability (ID) are common in the general population and have been linked to lesions in >700 genes. Emerging evidence suggests that this diverse group of genes converge on a limited set of neurodevelopmental pathways, including those that rely on RNA binding proteins (RBPs) to guide spatiotemporal patterns of neuronal mRNA trafficking and translation. Our labs co-discovered a monogenic form of ID caused by loss-of-function mutations in the ubiquitously expressed RBP ZC3H14. Studies exploiting the conserved ZC3H14 ortholog in Drosophila, Nab2, reveal that Nab2 localizes to neuronal nuclei and cytoplasmic ribonucleoprotein granules and is required specifically within brain neurons for olfactory memory and proper patterns of axon projection. At a molecular level, Nab2 can act as a translational repressor in conjunction with the Fragile-X mental retardation protein homolog Fmr1 and shares target RNAs with the Fmr1-interacting RBP Ataxin-2. However, neuronal signaling pathways regulated by Nab2, as well as mechanisms that elevate ZC3H14/Nab2 function in neurons relative to other cell types, remain elusive. We will present evidence that Nab2 controls neuronal expression of a well-conserved growth cone guidance factor, the guanine-nucleotide exchange factor (GEF) Trio, whose vertebrate homolog TRIO acts through the F-actin regulatory GTPases RHO and RAC to guide axon projection. Nab2 controls Trio levels in the fly brain by modulating an intron-retention event within the 5’ UTR of trio mRNA isoforms, and this mechanism appears to be dependent on N⁶-methyladenosine (m⁶A) deposition on the trio pre-mRNA. Data will be presented on the role of m6A and Nab2 in controlling Trio splicing and expression, along with Nab2-Trio coregulation of axonal development in the CNS. Given that human TRIO is mutated in a dominant form of ID, this potential link between Nab2 and Trio in Drosophila could suggest that Nab2/ZC3H14 and Trio/TRIO act in a conserved ID pathway required to pattern neuronal processes in the developing nervous system.

A conserved RNA binding protein regulates RNAs critical for neurodevelopment