Genetic analyses of copy-number variants, single-nucleotide variants and chromosomal translocations, as well as co-expression network analysis of postmortem brain tissue, have implicated the human RBFOX1 gene in autism spectrum disorders (ASD) and associated co-morbidities.
Mani Ramaswami and others have recently shown that, in addition to nuclear isoforms known to be involved in alternative splicing, the RBFOX1 gene encodes a conserved cytoplasmic variant form required for translational control in germ cells1 and potentially of neuronal mRNAs. In addition, preliminary findings from Ramaswami’s laboratory indicate that Drosophila RBFOX1 and the translational repressor protein Ataxin-2 have roles in olfactory habituation and the regulation of excitation-inhibition (E/I) balance, processes that are often altered in ASD. This makes it important to test whether the cytoplasmic or nuclear RBFOX1 isoforms are primarily involved in ASD-relevant behaviors and in the regulation of ASD-associated genes.
Building on their preliminary observations, Ramaswami and colleagues now aim to: 1. resolve the role of the cytoplasmic isoform of RBFOX1 in olfactory habituation and E/I balance in Drosophila; 2. determine whether RBFOX1 mediates translational repression by recruiting Ataxin-2 and associated proteins; 3. begin to test whether ASD-implicated, candidate RBFOX1 target genes are required for regulating compensatory inhibitory synaptic potentiation required for olfactory habituation in vivo; and 4. create reagents to test the hypothesis that RBFOX1 binds the 3’UTRs of ASD-implicated genes and regulates their translation in neurons.
These studies will establish the groundwork required to justify a more extensive study of the functions of cytoplasmic RBFOX1 and the in vivo significance of its potential translational regulation of target genes implicated in ASD. In the longer term, the team aims to utilize this research to help build a platform for the collaborative development of translational strategies based on information and insights from model organism research.